Review Mistery of Cancer 2013

Biochimica et Biophysica Acta 1836 (2013) 4959
Contents lists available at SciVerse ScienceDirect
Biochimica et Biophysica Acta

journal homepage: www.elsevier.com/locate/bbacan
Review
Unraveling the mystery of cancer metabolism in the genesis of

tumor-initiating cells and development of cancer
Gaochuan Zhang b, 1, Ping Yang a, 1, Pengda Guo a, 1, Lucio Miele c, Fazlul H. Sarkar d,
Zhiwei Wang a, e,, Quansheng Zhou a,
a
Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Afliated Hospital of Soochow University, Key Laboratory of Thrombosis and Hemostasis, Soochow University,
Ministry of Health, Suzhou, Jiangsu 215123, PR China
Department of Bioinformatics, School of Biology and Basic Medical Sciences, Medical College, Soochow University, Suzhou, Jiangsu 215123, PR China
c
University of Mississippi Cancer Institute, Jackson, MS 39216, USA
d
Department of Pathology and Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
e
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
b
a r t i c l e
i n f o
Article history:
Received 6 January 2013
Received in revised form 6 March 2013
Accepted 11 March 2013
Available online 21 March 2013
Keywords:
Cancer metabolism
Stem cells
Cancer therapy
Oncogenic metabolic genes
a b s t r a c t
Robust anaerobic metabolism plays a causative role in the origin of cancer cells; however, the oncogenic metabolic genes, factors, pathways, and networks in genesis of tumor-initiating cells (TICs) have not yet been systematically summarized. In addition, the mechanisms of oncogenic metabolism in the genesis of TICs are enigmatic.
In this review, we discussed multiple cancer metabolism-related genes (MRGs) that are overexpressed in TICs
and are responsible for inducing pluripotent stem cells. Moreover, we summarized that oncogenic metabolic
genes and onco-metabolites induce metabolic reprogramming, which switches normal mitochondrial oxidative
phosphorylation to cancer anaerobic metabolism, triggers epigenetic, genetic, and environmental alterations,
drives the generation of TICs, and boosts the development of cancer. Importantly, cancer metabolism is controlled by positive and negative metabolic regulators. Positive oncogenic metabolic regulators, including key oncogenic metabolic genes, onco-metabolites, hypoxia, and an acidic environment, promote oncogenic metabolic
reprogramming and anaerobic metabolism. However, dysfunction of negative metabolic regulators, including
defects in p53, PTEN, and LKB1-AMPK-mTOR pathways, enhances cancer metabolism. Loss of the metabolic balance results in oncogenic metabolic reprogramming, genesis of TICs, and tumorigenesis. Collectively, this review
provides new insight into the role and mechanism of these oncogenic metabolisms in the genesis of TICs and tumorigenesis. Accordingly, targeting key oncogenic genes, onco-metabolites, pathways, networks, and the acidic
cancer microenvironment appears to be an attractive strategy for novel anti-tumor treatment.
2013 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Overexpression of oncogenic metabolism-related genes triggers the genesis of TICs . .
2.1.
glycine decarboxylase
. . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Pyruvate kinase M2
. . . . . . . . . . . . . . . . . . . . . . . . . . . .
Metabolic gene mutant driver oncogenic metabolic reprogramming and genesis of TICs
3.1.
Oncogenic reprogramming of glucose metabolism . . . . . . . . . . . . . .
3.1.1.
MYC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.2.
RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.3.
AKT1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.4.
SRC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.5.
BCR-Abl and ALDH2 . . . . . . . . . . . . . . . . . . . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
50
50
50
51
51
51
51
51
51
52
52
Correspondence to: Z. Wang, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., Boston, MA 02215, USA. Tel.: +1 617
735 2474; fax: +1 617 735 2480.
Correspondence to: Q. Zhou, Cyrus Tang Hematology Center, Soochow University, Room 703-3505, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu 215123, PR China.
Tel.: +86 512 65882116; fax: +86 512 65880929.
E-mail addresses: zwang6@bidmc.harvard.edu (Z. Wang), quanshengzhou@yahoo.com (Q. Zhou).
1
These authors contributed equally to this work.
0304-419X/$ see front matter 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.bbcan.2013.03.001
50
G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959
3.2.
Oncogenic metabolic reprogramming of the glutaminolytic pathway . . .
3.3.
Oncogenic metabolic reprogramming of glycine metabolism . . . . . . .
4.
Onco-metabolites cause oncogenic metabolic reprogramming and tumorigenesis
4.1.
2-hydroxyglutarate (2-HG) . . . . . . . . . . . . . . . . . . . . . .
4.2.
Lactate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
Kynurenine (Kyn)
. . . . . . . . . . . . . . . . . . . . . . . . . .
5.
The potential role of non-coding RNA in oncogenic metabolic reprogramming and
5.1.
miRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
piRNAs and Piwi proteins . . . . . . . . . . . . . . . . . . . . . . .
6.
Loss of the metabolic YinYang balance promotes cancer initiation and progression .
6.1.
Positive oncogenic metabolic regulation . . . . . . . . . . . . . . . .
6.1.1.
Oncogenes and onco-metabolites . . . . . . . . . . . . . . .
6.1.2.
Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1.3.
Acidic microenvironment . . . . . . . . . . . . . . . . . . .
6.2.
Negative oncogenic metabolic regulation . . . . . . . . . . . . . . . .
6.2.1.
p53 . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.2.
PTEN . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.3.
LKB1 and AMPK . . . . . . . . . . . . . . . . . . . . . . .
7.
Conclusions and perspectives
. . . . . . . . . . . . . . . . . . . . . . . .
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
In 1927, the biochemist Otto Warburg found that cancer tissues had
a unique metabolic pattern distinct from normal tissues, by which cancer cells preferred a robust anaerobic metabolism even in the presence
of sufcient oxygen [1]. In 1956, Warburg suggested the theory that anaerobic metabolism played a causative role in the origin of cancer cells
[2]. Unfortunately, cancer metabolism had not been paid enough attention for decades until recently when cancer metabolism was recognized
as a hallmark of cancer [3], playing a pivotal role in cell reprogramming
and initiation of cancers [4]. In addition to the rapid progress in cancer
metabolism, another breakthrough in the cancer research eld is the
nding of tumor-initiating cells (TICs) or cancer stem cells (CSCs). In
1997, Bonnet and Dick found that a small subpopulation of CD34+
CD38 leukemic cells displayed strong self-renewal capability and differentiation potential, and could be leukemia-initiating cells [5]. Subsequently, TICs were also found in several solid tumors [6]. More recently,
a pivotal role of TICs in cancer initiation, development, metastasis and
drug resistance has been demonstrated in vivo [7,8]. However, the role
and mechanism of oncogenic metabolism in the genesis of TICs remain
to be further investigated.
Accumulated data have shown that sustained anaerobic metabolism
not only provides energy and various biomaterials to meet the demand
of tumor growth [9,10], but also contributes to the genesis of TICs and
tumorigenesis [3,4,11]. During the initiation and development of malignant tumors, cancer cells usually reprogram their metabolism need
through vigorous aerobic glycolysis to produce sufcient energy and
various biomaterials. For a long time, it was generally believed that
tumor cells underwent robust glycolysis due to a defect in mitochondrial glucose oxidative phosphorylation [1,2]. However, recent studies
have indicated that glucose oxidative phosphorylation in mitochondria
of most cancer cells was normal, and cells preferentially underwent anaerobic metabolism even in the presence of abundant oxygen. Cancer
cells reprogram glucose metabolism, amino acid, lipid, and nucleic
acid metabolism [911]. Cancer metabolism undertakes a complex process that even Warburg did not expect [4,12] and the landscape of cancer metabolism has recently been broadened far beyond the classic
Warburg effect in cancer metabolism.
Despite a tremendous advance in cancer metabolism recently, the
role and mechanism of cancer metabolism in the genesis of TICs and development of cancer remain unclear. In the present article, we extensively discussed recent progress in oncogenic metabolic reprogramming
during the generation of TICs and development of cancers, and addressed
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
tumorigenesis
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
52
53
53
53
53
53
54
54
54
54
54
54
54
54
55
55
55
56
56
56
56
56
the critical role of the loss of metabolic YinYang regulatory balance in

the initiation of cancer. Finally, we proposed new strategies and approaches to further study cancer metabolism in the generation of TICs
and malignant tumors, and to target onco-metabolites, oncogenic metabolic genes, pathways, networks, and the acidic tumor microenvironment for novel anti-tumor drug discovery and effective anti-cancer
therapy.
2. Overexpression of oncogenic metabolism-related genes triggers
the genesis of TICs
Recently, accumulated evidence suggests that metabolism-related
genes (MRGs) including glycine decarboxylase (GLDC) and pyruvate kinase M2 (PKM2) are overexpressed in TICs [1316]. It is known that generation of TICs is also driven by intrinsic and extrinsic factor-induced
epigenetic alterations and genomic DNA mutations. Whereas genetic
mutations have been traditionally considered a major driving force in tumorigenesis, recent studies have shown that epigenetic alteration usually precedes genetic mutations and is crucial to initiation of cancer
[13,14]. Epigenetic changes, including DNA methylation, histone modications (acetylation, phosphorylation, ubiquitination, biotinylation, and
SUMOylation), and non-coding RNA, promote overexpression of various
oncogenic metabolic genes including GLDC and PKM2, resulting in oncogenic metabolic reprogramming, genesis of TICs and tumorigenesis.
2.1. glycine decarboxylase
It has been known that GLDC expression is up-regulated by oncogenic MYC, Ras, and phosphatidylinositol 3-kinase (PI3K) during the cellular
transformation process [11]. Zhang et al. recently found overexpression
of GLDC in TICs of non-small cell lung cancer (NSCLC), which resulted
in an increase in pyrimidine synthesis and promoted cell proliferation,
colony formation, genesis of TICs, and initiation of NSCLC [11]. GLDC induced oncogenic metabolic reprogramming through stimulation of glycine metabolism and pyrimidine synthesis and promotion of glycolysis,
which effectively overcomes the crisis of nucleotide deciency and replication stress in rapidly proliferative cells during tumorigenesis. In NIH/
3T3 cells, overexpression of GLDC markedly increased malignant transformation in vitro and colony formation in vivo, while knockdown of
GLDC in lung cancer spheroid cells from patients with NSCLC inhibited
cell proliferation and colony formation, and signicantly impaired the tumorigenicity of the cells [11]. These data indicate that GLDC is likely an
oncogenic metabolic driver for genesis of TICs in lung cancer [11,15].
2.2. Pyruvate kinase M2

PKM2 belongs to the embryonic pyruvate kinase M2 isoform and
plays an important role in glucose metabolism during embryogenesis.
PKM2 expression is diminished after birth in normal people; however, various malignant tumors have atavism to overexpress PKM2
which is essential for cancer anaerobic metabolism and tumorigenesis. PKM2 overexpression facilitates lactate production in cancer
cells and promotes rapid tumor growth [16]. PKM2 gene transcription
is activated by hypoxia-inducible factor 1 (HIF-1). Interestingly,
PKM2 interacts directly with the HIF-1 subunit and enhances
transactivation of various HIF-1 target genes and participates in a
positive feedback loop that boosts HIF-1 mediated reprogramming
of glucose metabolic pathway in cancer cells [17]. In addition, the
cancer stem cell surface biomarker CD44 is closely related to PKM2
function and initiation of cancers. CD44 interacts with PKM2 and enhances the glycolytic phenotype of cancer cells. Silencing of CD44 by
small interfering RNA increased mitochondrial respiration and
inhibited glycolysis [18]. The impact of CD44 on oncogenic metabolic
reprogramming and genesis of TICs is worthy of further investigation.
Besides the important role of PKM2 in glycolysis, PKM2 also regulates
protein phosphorylation, transcription, and cell signal transduction.
Recently, Yang et al. reported that PKM2 bound to histone H3 and elevated histone H3 phospholyration upon epidermal growth factor receptor (EGFR) activation, which caused the dissociation of HDAC3
from the CCND1 and MYC promoter regions, and caused acetylation
of histone H3 at K9 and overexpression of c-Myc and cyclin D1,
resulting in tumor cell proliferation, cell-cycle progression, and
brain tumorigenesis [19,20]. Additionally, PKM2 promotes de novo
serine synthesis to stimulate mTORC1 activity and sustain cell proliferation [21]. Furthermore, activation of EGF-EGFR signal pathway
causes translocation of PKM2 into the nucleus. Nuclear PKM2 binds
to -catenin and leads to histone H3 acetylation and cyclin D1 expression; hence, PKM2-dependent -catenin transactivation is critical to
EGF-promoted tumor cell proliferation and brain tumor development
[22].
Recently, PKM2 was found to promote aerobic glycolysis in cancer
cells [23]. Interestingly, in rapidly dividing cancer cells, PKM2 expression was accompanied with the decreased pyruvate kinase enzyme
activity. Notably, phosphoenolpyruvate (PEP), a substrate for pyruvate kinase, can act as a phosphate donor and participate in the phosphorylation of the glycolytic enzyme PGAM1, which imply an
alternate glycolytic pathway in the proliferating cancer cells [23].
Moreover, one study demonstrated that SAICAR, an intermediate of
the de novo purine nucleotide synthesis pathway, can specically promote PKM2 expression in cancer cells, and subsequently change cellular energy, glucose uptake and lactate production, leading to
cancer cell survival [24]. Furthermore, it has been revealed that
PKM2 promotes Warburg effect due to ERK1/2 phosphorylation and
nuclear translocation of PKM2 [25].
In addition to GLDC and PKM2, overexpression of 3-hydroxy-3methylglutaryl-CoA reductase (HMGCR) is known to dysregulate the
mevalonate pathway and promotes oncogenic transformation and colony
formation in vitro and tumor growth in vivo [26]. Elevation of PTP4A1 and
PTP4A12 (protein tyrosine phosphatase type IVA, member 1, 2) levels in
stably transfected cells resulted in a transformed phenotype, suggesting
that they may play some role in tumorigenesis [27,28]. Collectively,
epigenetic alteration-induced overexpression of oncogenic metabolic
genes may cause aberrant metabolic reprogramming and drive the
genesis of TICs and development of cancer.
3. Metabolic gene mutant driver oncogenic
metabolic reprogramming and genesis of TICs
Abnormal epigenetic changes may cause genomic DNA to be
more susceptible to endogenous and exogenous genotoxic attack,
51
resulting in chromosome translocation, gene mutagenesis and generation of oncogenic metabolic genes. Oncogenic metabolic genes induce
reprogramming of glucose, glutamine, and glycine metabolism to
form discrete oncogenic metabolic pathways and networks, driving
the genesis of TICs and development of malignant tumors.
3.1. Oncogenic reprogramming of glucose metabolism
It is well known that cancer cells undergo robust glycolysis to obtain sufcient energy and build biomaterials for their rapid growth.
Overexpression or re-activation of key metabolism-related oncogenes, such as MYC, KRAS, AKT1, SRC, and BCR-ABL, promotes oncogenic reprogramming of glucose metabolism through up-regulation of
several key glycolytic genes, favoring the genesis of TICs and development of cancer (Table 1).
3.1.1. MYC
Overexpression of MYC enhances phosphatidylinositol (PI) metabolism in human kidney cancer cells [29]. MYC up-regulates the expression
of various glucose metabolic genes, including LDHA, PKM2, HK2, PDK1,
C6orf108 (RCL), GLUT1, GPI, phosphofructokinase, GAPDH, phosphoglycerate
kinase, and enolase, and reprograms glucose metabolic pathways [3033].
MYC boosts transcription of PTB, hnRNPA1, and hnRNPA2, enhances the
PKM splicing error, and results in the overexpression of embryonic pyruvate kinase isoform PKM2 that promotes aerobic glycolysis in tumors
[34,35]. In addition, MYC-induced hexokinase 2 (HK2) catalyzes the rst
step of glycolysis, while MYC-induced PDK1 inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration, resulting in a strong
Warburg effect [36]. The glycolysis in hypoxia in cancers also depends on
the cooperation between MYC and HIF1 [36]. Moreover, MYC-induced
overexpression of lactate dehydrogenase A (LDHA) markedly upgrades
glycolysis and leads to overproduction of lactate to form an acidic
tumor microenvironment, which is essential for lactate-driven genesis
of TICs and MYC-mediated oncogenic transformation and tumorigenesis [37,38]. MYC also reprograms glutamine, proline, glycine, and lipid
metabolic pathways, as well as elevates the expression of genes that
are related to fatty acid and glycerophospholipid synthesis, such as
MECR, ACSL1, AACS, ACAT1, AGAPT5, DGAT2, and LYPLA1, resulting in an
increase in lipid biosynthesis [39]. Additionally, MYC regulates the ketogenic metabolism pathway through down-regulation of HMGCS2 gene
expression [40,41]. Furthermore, MYC promotes the nucleotide biosynthetic pathway via up-regulation of TYMS, IMPDH1, IMPDH2, and PRPS2
in various tumors [4244], as well as inhibits p53 function, thereby advancing tumorigenesis [45]. Consistent with the pivotal role of MYC in
oncogenic metabolic reprogramming, our recent bioinformatic analysis
indicated that MYC was overexpressed in various human cancer stem
cells and malignant tumor tissues [13]. Together, MYC could be a master
oncogenic metabolic driver for metabolic reprogramming, genesis of
TICs, and tumorigenesis.
3.1.2. RAS
Overexpression of RAS family oncogenes (KRAS, HRAS, and NRAS) induces oncogenic metabolic reprogramming, stimulates glycolysis to produce lactate and alpha-ketoglutarate (-KG), and enhances synthesis of
nucleic acids and lipids [4648]. Activation of KRAS (G12V) decreases
mitochondrial glucose oxidative phosphorylation, but increases glycolysis in cells [49]. Additionally, RAS stimulates phospholipid metabolism
via up-regulation of either phospholipase C or phospholipase A2 activity
in the inositol phospholipid signaling pathway [5052]. Thus, RASmediated oncogenic metabolic reprogramming, including glycolysis
and lipid metabolism, is vital to support cancer cell growth [53].
3.1.3. AKT1
Frequent dysregulation of AKT1 has been observed in various human
cancers. AKT1, a serine/threonine kinase, has been found to promote cell
survival and suppress apoptosis through multiple mechanisms including
52
Table 1
Oncogenic metabolic reprogramming drives the genesis of tumor-initiating cells and tumorigenesis.
Gene name
Role in cancer metabolism
Genesis of tumor-initiating cells (TICs) and

tumorigenesis
Reference
MYC
Promotes glycolysis and glutamine, proline, glycine,

lipid metabolisms; nucleotide biosynthesis.
[2945,6466]
RAS (KRAS, HRAS, NRAS)
Activate glycolysis as well as glutamine,

phospholipid, polyamine, and nucleic acid
metabolism.
Enhances glycolysis.
Triggers oncogenic metabolic reprogramming,

increment of stemness, genesis of TICs, and
tumorigenesis.
Induce metabolic reprogramming that is essential
for RAS-mediated tumorigenesis.
Abnormal AKT1 activation promotes glycolysis and
cancer cell survival.
Induces remodeling of energetic metabolism in
cancer cells and increases cell proliferation.
Induces metabolic reprogramming and generation
of TICs in chronic myeloid leukemia.
As a cancer stem cell marker, CD44 is implicated in
the genesis of TICs and initiation of cancers.
Drives the genesis of TICs in non-small cell lung
cancer.
Mutation in IDH1 and IDH2 contributes to initiation
and progression of gliomas and leukemia.
Result in a transformed phenotype and may play
some role in tumorigenesis.
Mutations in ALDH2 increase DNA damage and
contribute to cancer predisposition in Fanconi
anemia patients.
Causes epigenetic alteration and promotes
transformation and tumorigenesis.
[54]
AKT1
SRC
BCR-ABL
CD44
GLDC
Stimulates glycolysis as well as energy and

phosphoinositide metabolism.
Increases glycolysis and RAC-mediated superoxide
production.
Interacts with PKM2 to enhance glycolysis.
PTP4A1, PTP4A2
Triggers glycine and pyrimidine metabolism as well

as glycolysis.
Catalyze NADPH-dependent reduction of KG to
2-hydroxyglutarate (2-HG).
Stimulate protein tyrosine phosphorylation.
ALDH2
Causes defective aldehyde metabolism
2-Hydroxyglutarate (2-HG)
Inhibits histone demethylation, leading to

genome-wide histone and DNA methylation
alterations.
Promotes tumor growth and causes oncogenic
metabolic reprogramming.
Functions as an endogenous ligand of the human
aryl hydrocarbon receptor (AHR).
IDH1, IDH2
Lactate
Kynurenine (Kyn)
Increases cell stemness and promotes stem cell

growth, genesis of TICs, and oncogenesis.
Contributes to malignant progression and poor
survival in human brain tumors.
[4653]
[55,56]
[57,60]
[18]
[11,71]
[7388]
[26,27]
[28]
[7388]
[8991]
[9396]
the regulation of glucose metabolism. AKT1 can increase mitochondriaassociated hexokinase (hexokinase I and II) activity and inhibit
cytochrome c release and apoptosis in cancer cells. Similar to MYC,
the activation of AKT1 can also lead to the Warburg effect through increased cellular glucose uptake, glycolysis, and lactate generation.
Once inhibiting glycolysis, AKT1-activated cells are susceptible to apoptosis which is different from MYC-activated cells that are sensitive to
the inhibition of mitochondrial function [54]. Therefore, it is required
to further investigate the molecular mechanism of AKT1-regulated cancer metabolism.
regulatory element-binding protein genes (SREBP1 and SREBP2), and

many other cancer metabolic genes, promoting oncogenic metabolic
reprogramming and leukemogenesis [58,59]. Moreover, overexpression
of BCR-Abl activates multiple cancer metabolism signal pathways [60].
In addition, the defect in aldehyde metabolism due to mutations in the
ALDH2 gene increases the acetaldehyde-mediated DNA damage that contributes to cancerous predisposition in patients with Fanconi's anemia, a
pre-leukemic condition [61], in which approximately 5% of the patients
develop leukemia subsequently.
3.1.4. SRC
The tyrosine kinase SRC is overexpressed in several cancer cells, and
differentiated cells rely mainly on oxidative phosphorylation to generate ATP. It has been demonstrated that the activation of SRC regulates
phosphoinositide metabolism through stimulating the expression of
basal phospholipase A2 (PLA2), and induces the remodeling of energetic metabolism through the stabilization of HIF1A and increased activities of several glycolytic enzymes including HK1 and HK2 [55]. The
activation of SRC can promote the metabolic reprogramming and subsequently elevate aerobic glycolysis in cancer cells. Moreover, SRC kinase
sustains mitochondrial respiration by phosphorylating the NDUFB10
subunit of complex I in human cancer cells [56]. Without a doubt, the
exact molecular mechanism by which SRC promotes reprogramming
of glucose metabolism needs to be further elucidated.
3.2. Oncogenic metabolic reprogramming of the glutaminolytic pathway
3.1.5. BCR-Abl and ALDH2

The well-known fusion protein BCR-Abl induces metabolic
reprogramming and generation of TICs in chronic myeloid leukemia
(CML), a myeloproliferative disorder of pluripotent stem cells [57].
Barger et al. found that BCR-Abl potently activates the protein kinase
S6K1 that drives glycolysis in leukemia cells. BCR-Abl-activated S6K1
stimulates transcription of metabolic genes, such as HIF1A, sterol
The other oncogenic metabolic reprogramming involves glutaminolysis. When tumor cells undergo robust glycolysis, glucose cannot
effectively enter the tricarboxylic acid (TCA) cycle to produce sufcient adenosine-5-triphosphate (ATP) and biomaterials required for
rapid tumor growth; alternatively, tumor cells manage to reprogram
glutaminolytic and biosynthetic pathways. Increased glutaminolysis
is now recognized as a key feature of the cancer metabolism and
contributes to the core metabolism of proliferating cells by supporting
energy production and biosynthesis [62]. Oncogenic MYC plays a pivotal
role in metabolic reprogramming of the glutaminolytic pathway. MYC
stimulates mitochondrial glutamine uptake and catabolism to meet the
cellular requirement for protein and nucleotide biosynthesis through
up-regulation of glutaminolytic genes, such as genes encoding the glutamine importers ASCT2 and SN2 [63]. MYC also enhances the expression of
mitochondrial glutaminase, which stimulates glutamine metabolism and
converts glutamine to glutamate, as well as increases mitochondrial production of acetyl-CoA for fatty acid biosynthesis [6466]. In addition, MYC
also promotes proline anabolism by inhibiting proline oxidase and enhancing the enzyme activity of proline biosynthesis from glutamine
[64]. Obviously, tumor cells reprogram the metabolic pathway to obtain
sufcient energy and bio-materials through glutaminolysis for their

sturdy growth [64,6770].
3.3. Oncogenic metabolic reprogramming of glycine metabolism
In addition to the reprogramming of glycolysis and the glutaminolytic
pathway in tumor cells, oncogenic metabolic reprogramming of glycine
metabolism emerges as another critical process in cancer metabolism and a driving force for tumor initiation. As stated previously,
overexpression of GLDC triggers the genesis of TICs in lung cancer
through its catalytical activity in glycine metabolism, pyrimidine
synthesis, and glycolysis [11]. More recently, Jain et al. used mass
spectrometry to measure the metabolic prole of the NCI-60 cancer
cell lines and revealed robust glycine metabolism which was closely
correlated with proliferation of cancer cells, and further documented
overexpression of genes in the glycine metabolic pathway that was
associated with poor prognosis in breast cancer patients. Whereas
inhibition of glycine uptake and its mitochondrial biosynthesis preferentially impaired rapidly proliferating cells [71], suggesting that
glycine metabolism plays an important role in cancer development.
Together, overexpression or activation of oncogenes, such as MYC,
KRAS, AKT1, SRC, and GLDC, drives oncogenic reprogramming of glucose, glutamine, and glycine metabolic pathways, resulting in the
genesis of TICs and initiation of malignant tumors.
4. Onco-metabolites cause oncogenic metabolic reprogramming
and tumorigenesis
It has been well established that tumor cells produce more lactate
and other metabolic materials than normal cells (14); however, the
associated metabolites have not been recognized as a driving force in
tumorigenesis until the last 5 years. Emerging evidence has shown
that several metabolites, such as 2-hydroxyglutarate (2-HG), lactate,
and kynurenine, may cause several epigenetic and genetic alterations,
resulting in the genesis of TICs and oncogenesis; hence, these oncogenic metabolites have recently been called onco-metabolites [72].
4.1. 2-hydroxyglutarate (2-HG)
Cytosolic isocitrate dehydrogenase 1 (IDH1) or its mitochondrial homolog IDH2 could sustain mutations, such as IDH1-R132, IDH2-R172,
and IDH2-R140, that can cause a defect in the conversion from isocitrate
to alpha-ketoglutarate (-KG). However, IDH mutants strongly catalyze
2-HG production and, consequently, 2-HG accumulates in various cancer patients [7376], including those with glioma [76], acute myeloid
leukemia (AML) [77,78], thyroid carcinoma [79], and chondrosarcoma
[80]. For example, Luchman et al. found that a glioma tumor stem cell
line (BT142) with an endogenous IDH1-R132H mutation produced
high 2-HG levels and demonstrated aggressive tumor-initiating capacity in vitro and in vivo; additionally, the glioma stem cells were readily
propagated in orthotopic xenografts of NOD/SCID mice [81]. Conditional IDH1 mutation (R132H) knock-in mice also showed increased 2-HG
production and early hematopoietic progenitors, as well as developed
anemia with extramedullary hematopoiesis [82]. Mutation of IDH1 or
IDH2 causes high 2-HG levels in some cancer patients, and the amount
of onco-metabolite 2-HG in cancer patients can be up to 100-fold higher
than that in normal individuals [83]. Overproduction of 2-HG is responsible for the oncogenic feature in IDH1 and IDH2 mutations, implying
that 2-HG could be a key player in the initiation of cancer in patients
with IDH mutations [84]. Mechanistic studies have shown that 2-HG
competitively inhibited -KG-dependent enzymes, such as histone
demethylases and DNA hydroxylases, leading to profound epigenetic alterations and tumorigenesis. Xu et al. demonstrated that 2-HG occupied
the same space as -KG in the active site of histone demethylases and
inhibited histone demethylation and 5-methylcytosine hydroxylation,
as well as caused an increase in histone methylation, but a decrease in
53
5-hydroxylmethylcytosine, resulting in genome-wide histone and

DNA methylation alterations [85]. 2-HG signicantly increased histone H3K9 methylation and elevated repressive histone methylation marks; notably, it effectively repressed the expression of various
lineage differentiation-specic genes and caused blockage of cell differentiation, thereby increasing the cancer stem/progenitor population
[86]. Consistent with these ndings, cells derived from IDH1-mutant
(R132H) knock-in mice have hypermethylated histones and abnormal
DNA methylation, similar to those observed in human IDH1-mutant
AML [87]. Particularly, R-2HG, but not S-2HG, enhances proliferation
and soft agar growth of human astrocytes [88]. Collectively, the oncometabolite 2-HG inhibits histone demethylation, increases DNA and
histone methylation, causes abnormal genome-wide histone and DNA
methylation, and stimulates overexpression of oncogenic genes,
resulting in cell reprogramming, expansion of stem/progenitor cells,
blockage of cell differentiation, and tumorigenesis [85].
4.2. Lactate
Traditionally, lactate from glycolysis has been considered a highenergy metabolic fuel for tumor cells. Emerging evidence has shown
that lactate in tumor tissues also plays a pivotal role in metabolic
reprogramming, which is an early event in the development of malignant
tumors; additionally, high lactate levels in cancer patients have been
identied as a prognostic parameter for metastasis and poor overall survival of cancer patients [89]. Ubaldo et al. recently reported that lactate
not only promoted stem cell growth, but also increased cell stemness.
Mechanistic studies revealed that lactate caused cell reprogramming
through overexpression of genes associated with stemness, including
genes that encode several stem cell-associated transcription factors
(SP1, MAZ, MEIS1, MLLT7, LEF1, TCF3, ELK1, SREBF1, PAX4, and ESRRA); additionally, lactate elevated nuclear histone acetylation and epigenetic alteration in MCF7 cancer cells and promoted dissociation of histones
from DNA, as well as enhanced gene transcription [89]. Lactate also promotes the production and secretion of VEGF, a potent tumor angiogenic
driver, and induces the formation of tumor new vasculature and growth
[90]. In addition to tumor cell production of lactate, cancer-associated broblasts undergo strong aerobic glycolysis and secrete lactate to feed
adjacent cancer cells, promoting cell reprogramming and increasing cell
stemness [91]. In addition, lactate recruits human MSCs towards
tumor cells to enhance stem cell migration [92]. Furthermore, L-lactate
stimulates cancer metastasis in the lung by 10-fold [92]. Collectively, the
onco-metabolite lactate causes oncogenic metabolic reprogramming
and enhances cell stemness, genesis of TICs, and tumor growth; and accumulation of lactate in solid tumors is an important early event in the development of cancer.
4.3. Kynurenine (Kyn)

Indoleamine 2, 3-dioxygenase catalyzes tryptophan metabolism
to produce kynurenine. Various human tumor cells constitutively
generate a high level of kynurenine, which functions as an endogenous ligand of the human aryl hydrocarbon receptor [93].
Kynurenine suppresses endogenous antitumor immunity and promotes tumor cell survival and tumorigenesis [93,94]. Patients with
endometrial, ovarian, and vulvar cancer have high levels of serum
kynurenine and a high Kyn/Trp ratio compared with controls,
suggesting that kynurenine may contribute to these gynecologic
cancers [95]. Interestingly, a pilot study showed that an increase in
tryptophan degradation and a high level of kynurenine were observed in early-stage breast cancer [96]. Together, these data suggest
that kynurenine may be a novel onco-metabolite to promote tumorigenesis and further investigation is warranted especially in brain
tumors.
54
5. The potential role of non-coding RNA in oncogenic metabolic

reprogramming and tumorigenesis
In addition to glycolysis, abnormal nucleic acid metabolism emerges
as a new player in oncogenic metabolic reprogramming in cells. Notably, aberrant microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs)
have been found in TICs and have been implicated in oncogenic metabolic reprogramming and tumorigenesis [97].
5.1. miRNAs
Epigenetic alterations may cause an abnormal miRNA expression prole and produce onco-miRNAs, such as miR-302s, miR-21, miR-27a,
miR-96, and miR-182, which induce oncogenic metabolic reprogramming
and tumorigenesis [98101]. For example, miR-23b stimulates glutamine
catabolism in human kidney tumors [64]. Additionally, miR-122 inhibits
mitochondrial metabolic function and is involved in the regulation of
fatty acid and cholesterol metabolism in hepatocellular carcinoma
[102,103]. Conversely, certain miRNAs have been implicated to have an
inhibitory effect on oncogenic metabolic reprogramming, including
let-7, miR-133a/b, miR-143, miR-145, miR-181a, miR-22, miR-23a/b,
miR-29b, miR-326, miR-34a, and miR-502 [104114]. For instance,
miR-326 inhibits embryonic and tumor-dominant PKM2 and induces apoptosis in glioma and glioma stem cells [109]. The miR-133a suppresses
glutathione S-transferase P1 and exerts a tumor suppressive effect in
head and neck squamous cell carcinoma [111]. The miR-143 impedes
glycolysis, cancer cell proliferation, and tumor formation through inhibition of HK2 expression in cancer cells [104,112,113]. The miR-34a participates in multiple tumor suppressive pathways by suppressing
inosine 5-monophosphate dehydrogenase, a rate-limiting enzyme of
de novo guanosine-5-triphosphate biosynthesis [107,114] in addition
to many direct targets of miR-34a. However, the mechanisms of
miRNA-dominant oncogenic metabolic reprogramming remain to be
further investigated.
5.2. piRNAs and Piwi proteins
Dysfunction of piRNAs and their partner Piwi proteins is associated
with the genesis of TICs and tumorigenesis. The piRNA 651 is aberrantly
overexpressed in multiple cancers, including gastric, colon, lung, and
breast cancer [115]. The piRNAs interact with the Piwi family of proteins
to regulate the stem-like epigenetic state of cancer and cell stemness.
For example, both mouse Piwil2 and the human Piwi ortholog Hiwi
have been found to be aberrantly expressed in various human cancers,
and abnormal expression of Piwil2 and Hiwi has been found to be associated with the development of TICs and tumorigenesis, and it was
further correlated with poor clinical prognosis of cancer patients
[116]. We have recently reported that tumor cells overexpressed several N-ternimal truncated Piwil2 variants, called Piwil2-like proteins,
which are implicated in tumorigenesis [117]. More recently, Siddiqi et
al. demonstrated that overexpression of Hiwi in mesenchymal stem
cells inhibited cell differentiation in vitro and promoted the generation
of sarcomas in vivo; in addition, Hiwi enhanced DNA methylation, acting as a tumor suppressor gene [118]. The piRNAs play important
roles in maintaining genome integrity by epigenetic silencing of transposons in the genome via DNA methylation. In addition to DNA methylation, Piwil2 enhances histone H3 acetylation and chromatin relaxation
[119]. Thus, piRNAs control cellular DNA methylation and histone H3
acetylation, and defects in piRNAs and Piwil2/Hiwi proteins contribute
to the genesis of TICs and oncogenesis.
6. Loss of the metabolic YinYang balance promotes cancer initiation
and progression
In healthy individuals, metabolism is tightly controlled by a positive
regulatory force (Yang) and negative regulatory force (Yin) to achieve
a YinYang balance. Intrinsic and extrinsic oncogenic factors may cause

loss of this metabolic YinYang balance, resulting in oncogenic metabolic
reprogramming and tumorigenesis. Accumulated data have shown that
positive oncogenic metabolic regulatory factors, such as oncogenes and
onco-metabolites, hypoxia, and an acidic environment, drive oncogenic
metabolic reprogramming and tumorigenesis; conversely, inactivation
of negative metabolic regulatory factors (Yin) also triggers oncogenic
metabolic reprogramming and cancer initiation. Thus, loss of the metabolic YinYang balance is critical to the initiation of TICs and development of malignant tumors (Fig. 1).
6.1. Positive oncogenic metabolic regulation
6.1.1. Oncogenes and onco-metabolites
As mentioned above, intrinsic and extrinsic oncogenic factors, such
as metabolism-related oncogenes, onco-metabolites, hypoxia, and an
acidic environment, act as positive oncgenic metabolic regulators to
promote oncogenic metabolic reprogramming and initiation of cancer.
Thus, the key oncogenes include MYC, MYCN, FOS, RAF, MOS, RAS, SRC,
MET, TRK, GLDC, IDH1, IDH2, Piwil2, HMGCR, PTP4A1, PTP4A2, and
ALDH2, whereas the key onco-metabolites include 2-HG, lactate, and
kynurenine (Fig. 1).
6.1.2. Hypoxia
The key extracellular positive oncogenic regulators are hypoxia and
an acidic microenvironment. When a tumor expands to larger than
2 mm in diameter, the central part of the tumor lacks oxygen; thus, the
tumor cells in a large tumor survive under hypoxic conditions. Hypoxia
induces overexpression of HIF1A, which functions as a master transcription factor to activate transcription of several hundred genes, including various metabolic, angiogenic, proliferative, and metastatic genes.
HIF1A induces the expression of glucose transporters GLUT1 and
GLUT3, glycolytic enzymes HK1 and HK2, phosphoglycerate kinase 1,
and LDHA, promoting glycolysis to produce lactate. In addition, HIF1A induces a switch from mitochondrial oxidative phosphorylation to aerobic
glycolysis under hypoxic conditions through reduction of oxygen consumption in mitochondria and activation of LDHA. HIF1-induced metabolic reprogramming is not only limited to carbohydrate metabolism, but
also lipid metabolism [120]. HIF1 induced-glycolysis is essential for the
generation of stem cells and maintenance of the stemness of hematopoietic stem cells, and HIF1 plays a crucial role in the survival and maintenance of leukemic stem cells in CML [121]. Under hypoxia, prostate
cancer cells express higher HIF1 and HIF-2 levels, and gain stem-like
cell properties, including overexpression of Oct3/4, Nanog, CD44, and
ABCG2, formation of additional colonies and spheres, and production of
an increased side population [122]. Similarly, under hypoxia, ovarian cancer cell lines ES-2 and OVCAR-3 overexpress Oct3/4, Sox2, and the cancer
stem cell marker CD133, as well as become putative cancer stem-like cells
[123]; additionally, nuclear HIF1A is closely related to overexpression of
CD133 in renal cell carcinoma [124]. Thus, hypoxia-induced HIF1A
plays an important role in metabolic reprogramming and genesis of TICs.
6.1.3. Acidic microenvironment
Tumor cell mediated oncogenic metabolism generates abundant
lactic acid and protons, leading to the reduction in the extracellular
pH values to as low as 6.0 (the usual range is 6.57.0) in tumor tissues
[125]. As mentioned above, the onco-metabolite lactate induces oncogenic metabolic reprogramming and boosts cell stemness. Acidic
pH activates mTOR and its downstream target (Eif4ebp1), insulin
modulators (Trib3 and Fetub) and facilitates anaerobic metabolism,
but diminishes catabolic processes; and these effects were independent of changes in oxygen concentration or glucose supply [126].
The tumor acidic microenvironment fosters initiation of TICs, tumor
progression, and metastasis [89]. Because hypoxia and low pH are
usually coupled in tumor tissues, the net impact of low pH on
55
Fig. 1. Loss of metabolic YinYang balance causes the initiation of TICs and development of malignant tumors. An increase in key oncogenic metabolic drivers and decrease in oncogenic metabolic inhibitors result in loss of the balance of metabolic-regulation and cause metabolic reprogramming, genesis of TICs, and tumorigenesis. Legends:
activation,
inactivation.
oncogenic metabolic reprogramming and genesis of TICs need to be

claried.
6.2. Negative oncogenic metabolic regulation
Increasing data have shown that p53, PTEN, LKB1, and AMPK are master genes responsible for the negative regulation of cancer metabolism.
6.2.1. p53
The tumor suppressor p53 is a master transcription factor that controls normal metabolism in cells through multiple metabolic and signaling pathways (Fig. 1). First, p53 inhibits the transcription of the
transporters GLUT 1 and 4, impeding cellular glucose uptake. Second,
p53 induces the expression of the TIGAR gene, which lowers the intracellular concentrations of fructose 2,6 bisphosphatase and decreases
glycolysis. Third, p53 increases ubiquitination of phosphoglycerate
mutase and reduces the activity of this glycolytic enzyme. Fourth, p53
enhances the expression of cytochrome c oxidase 2 (SCO2) and glutaminase
2 genes and increases the rate of the TCA cycle and oxidative phosphorylation. Cells with mutant p53 have a low efcacy of oxidative phosphorylation, but a robust glycolysis. Furthermore, p53 regulates the
transcription of the genes PTEN, IGF-binding protein-3, tuberous
sclerosis protein 2, as well as the gene encoding the beta subunit of
AMPK, all of which negatively regulate the AKT-mTOR signaling pathway [127,128]. Thus, p53 favors glucose oxidative phosphorylation and
impedes the Warburg effect, exerting an anti-tumor metabolic effect
along with tumor suppressive function [129]. The p53 mutation or
silencing of p53 expression leads to metabolic reprogramming and

tumorigenesis. Strikingly, mutation in the p53 gene occurs in approximately 50% of human cancers, and p53 knockout mice easily
grow various tumors; therefore, deciency in the anti-cancer metabolic function of p53 will facilitate metabolic reprogramming and
cause stem-like phenotypes in p53 mutant cells.
6.2.2. PTEN
The tumor suppressor gene PTEN encodes a lipid phosphatase that
degrades phosphatidylinositol-3,4,5-triphosphate and inhibits the
PI3K-Akt-mTOR pathway. PTEN governs cellular energy metabolism
and many other activities [130]. PTEN transgenic mice show increased
energy expenditure and reduced body fat accumulation. Cells derived
from these mice show reduced glycolysis and glucose but increased mitochondrial oxidative phosphorylation, and the cells are resistant to oncogenic transformation. Elevation of the PTEN level and activity inhibits
PI3K-Akt-mTOR-dependent and -independent pathways and reverses
cancer metabolism from glycolysis to oxidative phosphorylation. Thus,
PTEN acts as an inhibitor of oncogenic metabolism [131,132]. PTEN
loss leads to the activation of the PI3K/AKT signaling pathway and
switch to cancer metabolism, which correlates with human cancer initiation, progression, and metastasis [133]. In addition, PTEN loss in prostate cancer causes signicant enhancement in the RAS/MAPK pathway
and increases stem/progenitor subpopulation, causing epithelial-tomesenchymal transition (EMT) and macrometastasis [134]. Together,
PTEN is an important negative oncogenic metabolic regulator.
56
6.2.3. LKB1 and AMPK

Malignant tumor tissues usually consume more ATP than normal tissues, and thus the tumor is often under metabolic stress; however, the
tumor undergoes oncogenic metabolic reprogramming to adapt to the
stress through altering the LKB1-AMPK pathway [135]. Both LKB1 and
AMPK are tumor suppressors and participate in an energy-sensing cascade that responds to the depletion of ATP, acting as a master metabolic
regulator. LKB1 activates its downstream signaling protein AMPK. The
LKB1-AMPK pathway inhibits anabolic processes but stimulates catabolic processes, and plays a critical role in the inhibition of oncogenic
metabolism [136]. Recent studies have revealed the serine/threonine
kinase LKB1 to be at the crossroads linking energy metabolism and hematopoietic stem cell maintenance, and deletion of LKB1 has been
shown to promote tumorigenesis and metastasis [137139]. Germline
mutations in LKB1 lead to cancer-susceptible PeutzJeghers Syndrome
(PJS), EMT, and defects in cell differentiation. Multiple LKB1 mutations
have been identied in various malignant tumors, such as sporadic cancers and epithelial cancers [140147].
AMPK is a metabolic master switch that senses intracellular energy
status, and it is activated in the presence of decreased levels of ATP
and increased levels of AMP or ADP [148150]. AMPK is activated by
phosphorylation of the activation loop within the kinase domain by
the upstream kinase LKB1; once activated, AMPK phosphorylates a
broad range of downstream targets, in particular, mTOR, a central controller of energy metabolism, cell growth, and proliferation [151153].
Activation of AMPK with metformin inhibits the reprogramming of
mouse embryonic and human diploid broblasts into iPS cells, and
AMPK activators hinder oncogenic metabolic reprogramming even
with a deciency in p53 [154]. AMPK activation results in enhanced
ATP-producing pathways, but reduces ATP-consuming pathways, and
switches cancerous glycolysis to normal oxidative phosphorylation.
These data indicate that AMPK activation exerts an anti-cancer metabolic reprogramming effect and activation of AMPK could be a new
strategy for metabolic targeting of TICs and cancer cells [155157]. Clinical studies have shown that AMPK activation is associated with an increase in life span [158] and prolongation of survival of patients
diagnosed with lung cancer and many other malignant tumors [159].
In contrast, AMPK gene mutation has been found to be closely associated with various cancers and that the down-regulation of AMPK gene expression has been found in various cancers, including hepatic [160],
colonal [161], gastric [162], kidney [163], ovarian [164], and various
other malignant tumors [165167].
In summary, the LKB1-AMPK-mTOR pathway is a key metabolic
switch between normal and malignant cells. Activation of the
LKB1-AMPK-mTOR pathway suppresses malignant metabolic reprogramming, transformation, and tumor cell proliferation, whereas
defects in the LKB1-AMPK-mTOR pathway enhance cancer metabolism
and tumorigenesis. Thus, the LKB1-AMPK-mTOR pathway appears to be
an attractive target for anti-cancer metabolic agent and antineoplastic
drug discovery.
7. Conclusions and perspectives
In conclusion, emerging evidence has indicated that an excess of positive (Yang) oncogenic metabolic regulators, including metabolismrelated oncogenes, onco-metabolites, hypoxia, and an acidic environment, and deciency of negative (Yin) metabolic regulators, such as
p53, PTEN, LKB1, and AMPK could switch aerobic metabolism to anaerobic metabolism in cells through re-engineering of metabolic pathways
and networks. Therefore, the loss of metabolic YinYang balance triggers
cell reprogramming, genesis of TICs, and the development of cancer. Although cancer metabolism is regarded as the seventh hallmark of cancer,
the mechanisms of oncogenic metabolic reprogramming in the genesis
of TICs are still incomplete. We still face with many challenges, including
(1) identifying specic cancer metabolic drivers and metabolic regulators during cancer initiation and development, (2) deciphering the key
knots of oncogenic metabolic pathways and networks, (3) studying the

dynamics of oncogenic metabolism in driving the genesis of TICs, and
(4) nding specic biomarkers and targets of cancer metabolism for
novel anti-cancer drug discovery.
Oncogenic metabolic reprogramming is necessary for the genesis of
TICs and development of cancer, and the acidic microenvironment
caused by aerobic glycolysis nurtures the generation and maintenance
of TICs. Thus, cancer metabolism is an attractive target for cancer therapy. The anti-diabetic drug metformin has demonstrated anti-tumor
properties, and is increasingly being considered a drug to prevent and
treat obesity-related cancers. Metformin induces phosphorylation of
acetyl-CoA carboxylase alpha, inhibits the expression of lipogenic transcription factor SREBP1c, and blocks the formation of malonyl-CoA.
Metformin-induced activation of AMPK can reduce stemness of cancer
cells and inhibit tumor cell proliferation of breast cancer cells in vitro
and in vivo [168]. Interestingly, metformin also suppresses the growth
of TICs and various tumor cells [169,170]. However, the effects of metformin in anti-tumor therapies are not satisfactory by its low tumor
specicity and moderate anti-cancer efcacy, which have prevented
successful and wide clinical use in anti-cancer therapy. Thus, it is necessary to use a new strategy to identify highly specic oncogenic metabolic targets and to discover novel effective anti-cancer metabolic drugs.
Targeting key knots of cancer metabolism, including (1) inhibition of
specic oncogenic metabolic genes and key regulators, (2) blockage of
oncogenic metabolic pathways and disruption of cancer metabolic networks, (3) elimination of onco-metabolites, and (4) normalization of
the acidic tumor environment, may efciently suppress the genesis of
TICs and progression of cancer, and thus the future appears to be
brighter in the development of new therapeutics to balance the Yin
Yang phenomenon toward cancer therapy.
Conict of interest
The authors declare that they have no conict of interest.
Acknowledgements
This study was supported by grants from the National Natural Science Foundation of China (grant nos. 30971138 and 81172087), the
Chinese Academy of Science Special National Strategic Leader Project
(no. XDA01040200), the Suzhou City Scientic Research Funds (nos.
SWG0904, SS201004, and SS201138), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Cultivation Base of State Key Laboratory of Stem
Cell and Biomaterials built together by the Ministry of Science and
Technology and Jiangsu Province, and Jiangsu Province's Key Discipline of Medicine (XK201118).
References
[1] O. Warburg, F. Wind, E. Negelein, The metabolism of tumors in the body, J. Gen.
Physiol. 8 (1927) 519530.
[2] O. Warburg, On the origin of cancer cells, Science 123 (1956) 309314.
[3] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell 144
(2011) 646674.
[4] P.S. Ward, C.B. Thompson, Metabolic reprogramming: a cancer hallmark even
warburg did not anticipate, Cancer Cell 21 (2012) 297308.
[5] D. Bonnet, J.E. Dick, Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell, Nat. Med. 3 (1997)
730737.
[6] M.F. Clarke, J.E. Dick, P.B. Dirks, C.J. Eaves, C.H. Jamieson, D.L. Jones, J. Visvader,
I.L. Weissman, G.M. Wahl, Cancer stem cellsperspectives on current status
and future directions: AACR Workshop on cancer stem cells, Cancer Res. 66
(2006) 93399344.
[7] G. Driessens, B. Beck, A. Caauwe, B.D. Simons, C. Blanpain, Dening the mode of
tumour growth by clonal analysis, Nature 488 (2012) 527530.
[8] J. Chen, Y. Li, T.S. Yu, R.M. McKay, D.K. Burns, S.G. Kernie, L.F. Parada, A restricted
cell population propagates glioblastoma growth after chemotherapy, Nature
488 (2012) 522526.
[9] A.J. Levine, A.M. Puzio-Kuter, The control of the metabolic switch in cancers
by oncogenes and tumor suppressor genes, Science 330 (2010) 13401344.

[10] E.K. Oermann, J. Wu, K.L. Guan, Y. Xiong, Alterations of metabolic genes and metabolites in cancer, Semin. Cell Dev. Biol. 23 (2012) 370380.
[11] W.C. Zhang, N. Shyh-Chang, H. Yang, A. Rai, S. Umashankar, S. Ma, B.S. Soh, L.L. Sun,
B.C. Tai, M.E. Nga, K.K. Bhakoo, S.R. Jayapal, M. Nichane, Q. Yu, D.A. Ahmed, C. Tan,
W.P. Sing, J. Tam, A. Thirugananam, M.S. Noghabi, Y.H. Pang, H.S. Ang, W.
Mitchell, P. Robson, P. Kaldis, R.A. Soo, S. Swarup, E.H. Lim, B. Lim, Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis, Cell 148 (2012) 259272.
[12] W.H. Koppenol, P.L. Bounds, C.V. Dang, Otto Warburg's contributions to current
concepts of cancer metabolism, Nat. Rev. Cancer 11 (2011) 325337.
[13] G. Zhang, B. Shang, P. Yang, Z. Cao, Y. Pan, Q. Zhou, Induced pluripotent stem cell
consensus genes: implication for the risk of tumorigenesis and cancers in induced pluripotent stem cell therapy, Stem Cells Dev. 21 (2012) 955964.
[14] A. Vincent, I. Van Seuningen, On the epigenetic origin of cancer stem cells,
Biochim. Biophys. Acta 1826 (2012) 8388.
[15] J.E. Dominy, F. Vazquez, P. Puigserver, Glycine decarboxylase cleaves a malignant
metabolic path to promote tumor initiation, Cancer Cell 21 (2012) 143145.
[16] W. Luo, G.L. Semenza, Emerging roles of PKM2 in cell metabolism and cancer
progression, Trends Endocrinol. Metab. 23 (2012) 560566.
[17] W. Luo, H. Hu, R. Chang, J. Zhong, M. Knabel, R. O'Meally, R.N. Cole, A. Pandey,
G.L. Semenza, Pyruvate kinase M2 is a PHD3-stimulated coactivator for
hypoxia-inducible factor 1, Cell 145 (2011) 732744.
[18] M. Tamada, O. Nagano, S. Tateyama, M. Ohmura, T. Yae, T. Ishimoto, E. Sugihara,
N. Onishi, T. Yamamoto, H. Yanagawa, M. Suematsu, H. Saya, Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance
in cancer cells, Cancer Res. 72 (2012) 14381448.
[19] X. Gao, H. Wang, J.J. Yang, X. Liu, Z.R. Liu, Pyruvate kinase M2 regulates gene
transcription by acting as a protein kinase, Mol. Cell 45 (2012) 598609.
[20] W. Yang, Y. Xia, D. Hawke, X. Li, J. Liang, D. Xing, K. Aldape, T. Hunter, Y.W.
Alfred, Z. Lu, PKM2 phosphorylates histone h3 and promotes gene transcription
and tumorigenesis, Cell 150 (2012) 685696.
[21] J. Ye, A. Mancuso, X. Tong, P.S. Ward, J. Fan, J.D. Rabinowitz, C.B. Thompson,
Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1
activity and cell proliferation, Proc. Natl. Acad. Sci. U. S. A. 109 (2012)
69046909.
[22] W. Yang, Y. Xia, H. Ji, Y. Zheng, J. Liang, W. Huang, X. Gao, K. Aldape, Z. Lu, Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation, Nature
480 (2011) 118122.
[23] H.M. Vander, J.W. Locasale, K.D. Swanson, H. Shar, G.J. Heffron, D. Amador-Noguez,
H.R. Christofk, G. Wagner, J.D. Rabinowitz, J.M. Asara, L.C. Cantley, Evidence for an alternative glycolytic pathway in rapidly proliferating cells, Science 329 (2010)
14921499.
[24] K.E. Keller, I.S. Tan, Y.S. Lee, SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions, Science 338 (2012)
10691072.
[25] W. Yang, Y. Zheng, Y. Xia, H. Ji, X. Chen, F. Guo, C.A. Lyssiotis, K. Aldape, L.C.
Cantley, Z. Lu, ERK1/2-dependent phosphorylation and nuclear translocation
of PKM2 promotes the Warburg effect, Nat. Cell Biol. 14 (2012) 12951304.
[26] J.W. Clendening, A. Pandyra, P.C. Boutros, G.S. El, F. Khosravi, G.A. Trentin, A.
Martirosyan, A. Hakem, R. Hakem, I. Jurisica, L.Z. Penn, Dysregulation of the
mevalonate pathway promotes transformation, Proc. Natl. Acad. Sci. U. S. A.
107 (2010) 1505115056.
[27] C.A. Cates, R.L. Michael, K.R. Stayrook, K.A. Harvey, Y.D. Burke, S.K. Randall, P.L.
Crowell, D.N. Crowell, Prenylation of oncogenic human PTP(CAAX) protein tyrosine phosphatases, Cancer Lett. 110 (1996) 4955.
[28] R.H. Diamond, D.E. Cressman, T.M. Laz, C.S. Abrams, R. Taub, PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth, Mol. Cell. Biol. 14 (1994)
37523762.
[29] Y. Kubota, T. Shuin, M. Yao, H. Inoue, T. Yoshioka, The enhanced 32P labeling of
CDP-diacylglycerol in c-myc gene expressed human kidney cancer cells, FEBS
Lett. 212 (1987) 159162.
[30] P. Ahuja, P. Zhao, E. Angelis, H. Ruan, P. Korge, A. Olson, Y. Wang, E.S. Jin, F.M.
Jeffrey FM, M. Portman, W.R. Maclellan, Myc controls transcriptional regulation
of cardiac metabolism and mitochondrial biogenesis in response to pathological
stress in mice, J Clin Invest. 120 (2010) 14941505.
[31] R.C. Osthus, H. Shim, S. Kim, Q. Li, R. Reddy, M. Mukherjee, Y. Xu, D. Wonsey, L.A.
Lee, C.V. Dang, Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc, J. Biol. Chem. 275 (2000) 2179721800.
[32] L.S. Pike, A.L. Smift, N.J. Croteau, D.A. Ferrick, M. Wu, Inhibition of fatty acid oxidation by etomoxir impairs NADPH production and increases reactive oxygen
species resulting in ATP depletion and cell death in human glioblastoma cells,
Biochim. Biophys. Acta. 1807 (2011) 726734.
[33] H. Shim, C. Dolde, B.C. Lewis, C.S. Wu, G. Dang, R.A. Jungmann, R. Dalla-Favera,
C.V. Dang, c-Myc transactivation of LDH-A: implications for tumor metabolism
and growth, Proc. Natl. Acad. Sci. U. S. A. 94 (1997) 66586663.
[34] C.J. David, M. Chen, M. Assanah, P. Canoll, J.L. Manley, HnRNP proteins controlled by
c-Myc deregulate pyruvate kinase mRNA splicing in cancer, Nature 463 (2010)
364368.
[35] H.R. Christofk, H.M. Vander, M.H. Harris, A. Ramanathan, R.E. Gerszten, R. Wei,
M.D. Fleming, S.L. Schreiber, L.C. Cantley, The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth, Nature 452
(2008) 230233.
[36] J.W. Kim, P. Gao, Y.C. Liu, G.L. Semenza, C.V. Dang, Hypoxia-inducible factor 1
and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase
1, Mol. Cell. Biol. 27 (2007) 73817393.
57
[37] B.C. Lewis, J.E. Prescott, S.E. Campbell, H. Shim, R.Z. Orlowski, C.V. Dang, Tumor
induction by the c-Myc target genes rcl and lactate dehydrogenase A, Cancer
Res. 60 (2000) 61786183.
[38] H. Shim, Y.S. Chun, B.C. Lewis, C.V. Dang, A unique glucose-dependent apoptotic
pathway induced by c-Myc, Proc. Natl. Acad. Sci. U S A. 95 (1998) 15111516.
[39] F. Morrish, N. Isern, M. Sadilek, M. Jeffrey, D.M. Hockenbery, c-Myc activates
multiple metabolic networks to generate substrates for cell-cycle entry, Oncogene 28 (2009) 24852491.
[40] N. Camarero, C. Mascaro, C. Mayordomo, F. Vilardell, D. Haro, P.F. Marrero, Ketogenic
HMGCS2 Is a c-Myc target gene expressed in differentiated cells of human colonic epithelium and down-regulated in colon cancer, Mol. Cancer Res. 4 (2006) 645653.
[41] N.T. Telang, F. Arcuri, O.M. Granata, H.L. Bradlow, M.P. Osborne, L. Castagnetta,
Alteration of oestradiol metabolism in myc oncogene-transfected mouse mammary epithelial cells, Br. J. Cancer 77 (1998) 15491554.
[42] C.V. Dang, A. Le, P. Gao, MYC-induced cancer cell energy metabolism and therapeutic opportunities, Clin. Cancer Res. 15 (2009) 64796483.
[43] Y.C. Liu, F. Li, J. Handler, C.R. Huang, Y. Xiang, N. Neretti, J.M. Sedivy, K.I. Zeller,
C.V. Dang, Global regulation of nucleotide biosynthetic genes by c-Myc, PLoS
One 3 (2008) e2722.
[44] S. Mannava, V. Grachtchouk, L.J. Wheeler, M. Im, D. Zhuang, E.G. Slavina, C.K.
Mathews, D.S. Shewach, M.A. Nikiforov, Direct role of nucleotide metabolism in
C-MYC-dependent proliferation of melanoma cells, Cell Cycle 7 (2008) 23922400.
[45] O. Vafa, M. Wade, S. Kern, M. Beeche, T.K. Pandita, G.M. Hampton, G.M. Wahl,
c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate
p53 function: a mechanism for oncogene-induced genetic instability, Mol. Cell
9 (2002) 10311044.
[46] S. Telang, A. Yalcin, A.L. Clem, R. Bucala, A.N. Lane, J.W. Eaton, J. Chesney, Ras
transformation requires metabolic control by 6-phosphofructo-2-kinase, Oncogene 25 (2006) 72257234.
[47] F. Weinberg, R. Hamanaka, W.W. Wheaton, S. Weinberg, J. Joseph, M. Lopez, B.
Kalyanaraman, G.M. Mutlu, G.R. Budinger, N.S. Chandel, Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity, Proc.
Natl. Acad. Sci. U. S. A. 107 (2010) 87888793.
[48] P. Vizan, L.G. Boros, A. Figueras, G. Capella, R. Mangues, S. Bassilian, S. Lim, W.N. Lee,
M. Cascante, K-ras codon-specic mutations produce distinctive metabolic phenotypes in NIH3T3 mice [corrected] broblasts, Cancer Res. 65 (2005) 55125515.
[49] Y. Hu, W. Lu, G. Chen, P. Wang, Z. Chen, Y. Zhou, M. Ogasawara, D. Trachootham, L.
Feng, H. Pelicano, P.J. Chiao, M.J. Keating, G. Garcia-Manero, P. Huang, K-ras(G12V)
transformation leads to mitochondrial dysfunction and a metabolic switch from
oxidative phosphorylation to glycolysis, Cell Res. 22 (2012) 399412.
[50] M. Huang, K. Chida, N. Kamata, K. Nose, M. Kato, Y. Homma, T. Takenawa, T. Kuroki,
Enhancement of inositol phospholipid metabolism and activation of protein kinase
C in ras-transformed rat broblasts, J. Biol. Chem. 263 (1988) 1797517980.
[51] T. Alonso, R.O. Morgan, J.C. Marvizon, H. Zarbl, E. Santos, Malignant transformation by ras and other oncogenes produces common alterations in inositol phospholipid signaling pathways, Proc. Natl. Acad. Sci. U. S. A. 85 (1988) 42714275.
[52] C.L. Yu, M.H. Tsai, D.W. Stacey, Cellular ras activity and phospholipid metabolism, Cell 52 (1988) 6371.
[53] D. Gaglio, C.M. Metallo, P.A. Gameiro, K. Hiller, L.S. Danna, C. Balestrieri, L. Alberghina,
G. Stephanopoulos, F. Chiaradonna, Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth, Mol. Syst. Biol. 7 (2011) 523.
[54] Y. Fan, K.G. Dickman, W.X. Zong, Akt and c-Myc differentially activate cellular
metabolic programs and prime cells to bioenergetic inhibition, J. Biol. Chem.
285 (2010) 73247333.
[55] R. Karni, Y. Dor, E. Keshet, O. Meyuhas, A. Levitzki, Activated pp 60c-Src leads to
elevated hypoxia-inducible factor (HIF)-1alpha expression under normoxia, J. Biol.
Chem. 277 (2002) 4291942925.
[56] E. Hebert-Chatelain, C. Jose, C.N. Gutierrez, J.W. Dupuy, C. Rocher, J. Dachary-Prigent, T.
Letellier, Preservation of NADH ubiquinone-oxidoreductase activity by Src kinasemediated phosphorylation of NDUFB10, Biochim. Biophys. Acta 1817 (2012)
718725.
[57] C.G. Geary, The story of chronic myeloid leukaemia, Br. J. Haematol. 110 (2000)
211.
[58] P. Tandon, C.A. Gallo, S. Khatri, J.F. Barger, H. Yepiskoposyan, D.R. Plas, Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deciency, Proc. Natl. Acad. Sci. U. S. A. 108 (2011)
23612365.
[59] K. Duvel, J.L. Yecies, S. Menon, P. Raman, A.I. Lipovsky, A.L. Souza, E. Triantafellow, Q.
Ma, R. Gorski, S. Cleaver, H.M. Vander, J.P. MacKeigan, P.M. Finan, C.B. Clish, L.O.
Murphy, B.D. Manning, Activation of a metabolic gene regulatory network downstream of mTOR complex 1, Mol. Cell 39 (2010) 171183.
[60] J.F. Barger, C.A. Gallo, P. Tandon, H. Liu, A. Sullivan, H.L. Grimes, D.R. Plas, S6K1
determines the metabolic requirements for BCR-ABL survival, Oncogene 32
(2013) 453461.
[61] F. Langevin, G.P. Crossan, I.V. Rosado, M.J. Arends, K.J. Patel, Fancd2 counteracts the
toxic effects of naturally produced aldehydes in mice, Nature 475 (2011) 5358.
[62] D. Daye, K.E. Wellen, Metabolic reprogramming in cancer: unraveling the role of
glutamine in tumorigenesis, Semin. Cell Dev. Biol. 23 (2012) 362369.
[63] D.R. Wise, R.J. DeBerardinis, A. Mancuso, N. Sayed, X.Y. Zhang, H.K. Pfeiffer, I.
Nissim, E. Daikhin, M. Yudkoff, S.B. McMahon, C.B. Thompson, Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction, Proc. Natl. Acad. Sci. U. S. A. 105 (2008) 1878218787.
[64] W. Liu, A. Le, C. Hancock, A.N. Lane, C.V. Dang, T.W. Fan, J.M. Phang, Reprogramming
of proline and glutamine metabolism contributes to the proliferative and metabolic
responses regulated by oncogenic transcription factor c-MYC, Proc. Natl. Acad. Sci.
U. S. A. 109 (2012) 89838988.
58
[65] F. Morrish, J. Noonan, C. Perez-Olsen, P.R. Gafken, M. Fitzgibbon, J. Kelleher, M.

VanGilst, D. Hockenbery, Myc-dependent mitochondrial generation of acetyl-CoA
contributes to fatty acid biosynthesis and histone acetylation during cell cycle
entry, J. Biol. Chem. 285 (2010) 3626736274.
[66] P. Gao, I. Tchernyshyov, T.C. Chang, Y.S. Lee, K. Kita, T. Ochi, K.I. Zeller, A.M. De Marzo,
J.E. Van Eyk, J.T. Mendell, C.V. Dang, c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism, Nature 458 (2009)
762765.
[67] J. Keijer J, M. Bekkenkamp-Grovenstein, D. Venema, Y.E. Dommels, Bioactive
food components, cancer cell growth limitation and reversal of glycolytic metabolism, Biochim. Biophys. Acta 1807 (2011) 697706.
[68] C.V. Dang, Therapeutic targeting of myc-reprogrammed cancer cell metabolism,
Cold Spring Harb. Symp. Quant. Biol. 76 (2011) 369374.
[69] C. Jose, N. Bellance, R. Rossignol, Choosing between glycolysis and oxidative phosphorylation: a tumor's dilemma? Biochim. Biophys. Acta. 1807 (2011) 552561.
[70] R.J. DeBerardinis, A. Mancuso, E. Daikhin, I. Nissim, M. Yudkoff, S. Wehrli, C.B.
Thompson, Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis, Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 1934519350.
[71] M. Jain, R. Nilsson, S. Sharma, N. Madhusudhan, T. Kitami, A.L. Souza, R. Kafri,
M.W. Kirschner, C.B. Clish, V.K. Mootha, Metabolite proling identies a key
role for glycine in rapid cancer cell proliferation, Science 336 (2012) 10401044.
[72] U.E. Martinez-Outschoorn, R.G. Pestell, A. Howell, M.L. Tykocinski, F. Nagajyothi,
F.S. Machado, H.B. Tanowitz, F. Sotgia, M.P. Lisanti, Energy transfer in parasitic
cancer metabolism: mitochondria are the powerhouse and Achilles' heel of
tumor cells, Cell Cycle 10 (2011) 42084216.
[73] M. Kranendijk, E.A. Struys, E. van Schaftingen, K.M. Gibson, W.A. Kanhai, M.S.
van der Knaap, J. Amiel, N.R. Buist, A.M. Das, J.B. de Klerk, A.S. Feigenbaum,
D.K. Grange, F.C. Hofstede, E. Holme, E.P. Kirk, S.H. Korman, E. Morava, A.
Morris, J. Smeitink, R.N. Sukhai, H. Vallance, C. Jakobs, G.S. Salomons, IDH2 mutations in patients with D-2-hydroxyglutaric aciduria, Science 330 (2010) 336.
[74] L. Dang, D.W. White, S. Gross, B.D. Bennett, M.A. Bittinger, E.M. Driggers, V.R. Fantin,
H.G. Jang, S. Jin, M.C. Keenan, K.M. Marks, R.M. Prins, P.S. Ward, K.E. Yen, L.M. Liau, J.D.
Rabinowitz, L.C. Cantley, C.B. Thompson, H.M. Vander, S.M. Su, Cancer-associated
IDH1 mutations produce 2-hydroxyglutarate, Nature 462 (2009) 739744.
[75] H. Yan, D.W. Parsons, G. Jin, R. McLendon, B.A. Rasheed, W. Yuan, I. Kos, I.
Batinic-Haberle, S. Jones, G.J. Riggins, H. Friedman, A. Friedman, D. Reardon, J.
Herndon, K.W. Kinzler, V.E. Velculescu, B. Vogelstein, D.D. Bigner, IDH1 and
IDH2 mutations in gliomas, N. Engl. J. Med. 360 (2009) 765773.
[76] F.E. Bleeker, S. Lamba, S. Leenstra, D. Troost, T. Hulsebos, W.P. Vandertop, M.
Frattini, F. Molinari, M. Knowles, A. Cerrato, M. Rodolfo, A. Scarpa, L. Felicioni,
F. Buttitta, S. Malatesta, A. Marchetti, A. Bardelli, IDH1 mutations at residue
p.R132 (IDH1(R132)) occur frequently in high-grade gliomas but not in other
solid tumors, Hum. Mutat. 30 (2009) 711.
[77] M.E. Figueroa, O. Abdel-Wahab, C. Lu, P.S. Ward, J. Patel, A. Shih, Y. Li, N. Bhagwat, A.
Vasanthakumar, H.F. Fernandez, M.S. Tallman, Z. Sun, K. Wolniak, J.K. Peeters, W.
Liu, S.E. Choe, V.R. Fantin, E. Paietta, B. Lowenberg, J.D. Licht, L.A. Godley, R.
Delwel, P.J. Valk, C.B. Thompson, R.L. Levine, A. Melnick, Leukemic IDH1 and IDH2
mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation, Cancer Cell 18 (2010) 553567.
[78] G. Marcucci, K. Maharry, Y.Z. Wu, M.D. Radmacher, K. Mrozek, D. Margeson, K.B.
Holland, S.P. Whitman, H. Becker, S. Schwind, K.H. Metzeler, B.L. Powell, T.H.
Carter, J.E. Kolitz, M. Wetzler, A.J. Carroll, M.R. Baer, M.A. Caligiuri, R.A. Larson,
C.D. Bloomeld, IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a cancer
and leukemia group B study, J. Clin. Oncol. 28 (2010) 23482355.
[79] J.P. Hemerly, A.U. Bastos, J.M. Cerutti, Identication of several novel non-p.R132
IDH1 variants in thyroid carcinomas, Eur. J. Endocrinol. 163 (2010) 747755.
[80] M.F. Amary, K. Bacsi, F. Maggiani, S. Damato, D. Halai, F. Berisha, R. Pollock, P.
O'Donnell, A. Grigoriadis, T. Diss, M. Eskandarpour, N. Presneau, P.C. Hogendoorn,
A. Futreal, R. Tirabosco, A.M. Flanagan, IDH1 and IDH2 mutations are frequent
events in central chondrosarcoma and central and periosteal chondromas but not
in other mesenchymal tumours, J. Pathol. 224 (2011) 334343.
[81] H.A. Luchman, O.D. Stechishin, N.H. Dang, M.D. Blough, C. Chesnelong, J.J. Kelly, S.A.
Nguyen, J.A. Chan, A.M. Weljie, J.G. Cairncross, S. Weiss, An in vivo patient-derived
model of endogenous IDH1-mutant glioma, Neuro Oncol. 14 (2012) 184191.
[82] P.S. Ward, J.R. Cross, C. Lu, O. Weigert, O. Abel-Wahab, R.L. Levine, D.M. Weinstock,
K.A. Sharp, C.B. Thompson, Identication of additional IDH mutations associated
with oncometabolite R(-)-2-hydroxyglutarate production, Oncogene 31 (2012)
24912498.
[83] S. Gross, R.A. Cairns, M.D. Minden, E.M. Driggers, M.A. Bittinger, H.G. Jang, M. Sasaki,
S. Jin, D.P. Schenkein, S.M. Su, L. Dang, V.R. Fantin, T.W. Mak, Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with
isocitrate dehydrogenase 1 and 2 mutations, J. Exp. Med. 207 (2010) 339344.
[84] G. Jin, Z.J. Reitman, I. Spasojevic, I. Batinic-Haberle, J. Yang, O. Schmidt-Kittler,
D.D. Bigner, H. Yan, 2-hydroxyglutarate production, but not dominant negative
function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations, PLoS One 6 (2011) e16812.
[85] W. Xu, H. Yang, Y. Liu, Y. Yang, P. Wang, S.H. Kim, S. Ito, C. Yang, P. Wang, M.T. Xiao, L.X.
Liu, W.Q. Jiang, J. Liu, J.Y. Zhang, B. Wang, S. Frye, Y. Zhang, Y.H. Xu, Q.Y. Lei, K.L. Guan,
S.M. Zhao, Y. Xiong, Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of
alpha-ketoglutarate-dependent dioxygenases, Cancer Cell 19 (2011) 1730.
[86] C. Lu, P.S. Ward, G.S. Kapoor, D. Rohle, S. Turcan, O. Abdel-Wahab, C.R. Edwards, R.
Khanin, M.E. Figueroa, A. Melnick, K.E. Wellen, D.M. O'Rourke, S.L. Berger, T.A. Chan,
R.L. Levine, I.K. Mellinghoff, C.B. Thompson, IDH mutation impairs histone demethylation and results in a block to cell differentiation, Nature 483 (2012) 474478.
[87] M. Sasaki, C.B. Knobbe, J.C. Munger, E.F. Lind, D. Brenner, A. Brustle, I.S. Harris, R.
Holmes, A. Wakeham, J. Haight, A. You-Ten, W.Y. Li, S. Schalm, S.M. Su, C.
Virtanen, G. Reifenberger, P.S. Ohashi, D.L. Barber, M.E. Figueroa, A. Melnick,
J.C. Zuniga-Pucker, T.W. Mak, IDH1(R132H) mutation increases murine
haematopoietic progenitors and alters epigenetics, Nature 488 (2012) 656659.
[88] P. Koivunen, S. Lee, C.G. Duncan, G. Lopez, G. Lu, S. Ramkissoon, J.A. Losman, P. Joensuu,
U. Bergmann, S. Gross, J. Travins, S. Weiss, R. Looper, K.L. Ligon, R.G. Verhaak, H. Yan,
W.J. Kaelin, Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to
EGLN activation, Nature 483 (2012) 484488.
[89] U.E. Martinez-Outschoorn, M. Prisco, A. Ertel, A. Tsirigos, Z. Lin, S. Pavlides, C.
Wang, N. Flomenberg, E.S. Knudsen, A. Howell, R.G. Pestell, F. Sotgia, M.P.
Lisanti, Ketones and lactate increase cancer cell stemness, driving recurrence,
metastasis and poor clinical outcome in breast cancer: achieving personalized
medicine via Metabolo-Genomics, Cell Cycle 10 (2011) 12711286.
[90] F. Hirschhaeuser, U.G. Sattler, W. Mueller-Klieser, Lactate: a metabolic key player in cancer, Cancer Res. 71 (2011) 69216925.
[91] D. Whitaker-Menezes, U.E. Martinez-Outschoorn, Z. Lin, A. Ertel, N. Flomenberg,
A.K. Witkiewicz, R.C. Birbe, A. Howell, S. Pavlides, R. Gandara, R.G. Pestell, F.
Sotgia, N.J. Philp, M.P. Lisanti, Evidence for a stromal-epithelial lactate shuttle
in human tumors: MCT4 is a marker of oxidative stress in cancer-associated broblasts, Cell Cycle 10 (2011) 17721783.
[92] Y.I. Rattigan, B.B. Patel, E. Ackerstaff, G. Sukenick, J.A. Koutcher, J.W. Glod, D.
Banerjee, Lactate is a mediator of metabolic cooperation between stromal carcinoma associated broblasts and glycolytic tumor cells in the tumor microenvironment, Exp. Cell Res. 318 (2012) 326335.
[93] C.A. Opitz, U.M. Litzenburger, F. Sahm, M. Ott, I. Tritschler, S. Trump, T. Schumacher, L.
Jestaedt, D. Schrenk, M. Weller, M. Jugold, G.J. Guillemin, C.L. Miller, C. Lutz, B.
Radlwimmer, I. Lehmann, A. von Deimling, W. Wick, M. Platten, An endogenous
tumour-promoting ligand of the human aryl hydrocarbon receptor, Nature 478
(2011) 197203.
[94] G.C. Prendergast, Cancer: why tumours eat tryptophan, Nature 478 (2011) 192194.
[95] R.A. de Jong, H.W. Nijman, H.M. Boezen, M. Volmer, H.K. Ten, J. Krijnen, A.G. van der
Zee, H. Hollema, I.P. Kema, Serum tryptophan and kynurenine concentrations as
parameters for indoleamine 2,3-dioxygenase activity in patients with endometrial,
ovarian, and vulvar cancer, Int. J. Gynecol. Cancer 21 (2011) 13201327.
[96] D.E. Lyon, J.M. Walter, A.R. Starkweather, C.M. Schubert, N.L. McCain, Tryptophan
degradation in women with breast cancer: a pilot study, BMC Res. Notes 4
(2011) 156.
[97] P.K. Singh, R.E. Brand, K. Mehla, MicroRNAs in pancreatic cancer metabolism,
Nat. Rev. Gastroenterol. Hepatol. 9 (2012) 334344.
[98] I.K. Guttilla, B.A. White, Coordinate regulation of FOXO1 by miR-27a, miR-96,
and miR-182 in breast cancer cells, J. Biol. Chem. 284 (2009) 2320423216.
[99] P.P. Medina, M. Nolde, F.J. Slack, OncomiR addiction in an in vivo model of
microRNA-21-induced pre-B-cell lymphoma, Nature 467 (2010) 8690.
[100] Y. Yu, S.S. Kanwar, B.B. Patel, P.S. Oh, J. Nautiyal, F.H. Sarkar, A.P. Majumdar,
MicroRNA-21 induces stemness by downregulating transforming growth factor
beta receptor 2 (TGFbetaR2) in colon cancer cells, Carcinogenesis 33 (2012) 6876.
[101] N. Koide, K. Yasuda, K. Kadomatsu, Y. Takei, Establishment and optimal culture conditions of microrna-induced pluripotent stem cells generated from HEK293 cells via
transfection of microrna-302 s expression vector, Nagoya J. Med. Sci. 74 (2012)
157165.
[102] D.R. Boutz, P.J. Collins, U. Suresh, M. Lu, C.M. Ramirez, C. Fernandez-Hernando, Y.
Huang, R.S. Abreu, Le SY, B.A. Shapiro, A.M. Liu, J.M. Luk, S.F. Aldred, N.D.
Trinklein, E.M. Marcotte, L.O. Penalva, Two-tiered approach identies a network
of cancer and liver disease-related genes regulated by miR-122, J. Biol. Chem.
286 (2011) 1806618078.
[103] J. Burchard, C. Zhang, A.M. Liu, R.T. Poon, N.P. Lee, K.F. Wong, P.C. Sham, B.Y. Lam,
M.D. Ferguson, G. Tokiwa, R. Smith, B. Leeson, R. Beard, J.R. Lamb, L. Lim, M. Mao,
H. Dai, J.M. Luk, microRNA-122 as a regulator of mitochondrial metabolic gene
network in hepatocellular carcinoma, Mol. Syst. Biol. 6 (2010) 402.
[104] A. Peschiaroli, A. Giacobbe, A. Formosa, E.K. Markert, L. Bongiorno-Borbone, A.J.
Levine, E. Candi, A. D'Alessandro, L. Zolla, A.A. Finazzi, G. Melino, miR-143 regulates hexokinase 2 expression in cancer cells, Oncogene 32 (2013) 797802.
[105] H. Zhai, B. Song, X. Xu, W. Zhu, J. Ju, Inhibition of autophagy and tumor growth in
colon cancer by miR-502, Oncogene 32 (2013) 15701579.
[106] C. Zou, Q. Xu, F. Mao, D. Li, C. Bian, L.Z. Liu, Y. Jiang, X. Chen, Y. Qi, X. Zhang, X.
Wang, Q. Sun, H.F. Kung, M.C. Lin, A. Dress, F. Wardle, B.H. Jiang, L. Lai,
MiR-145 inhibits tumor angiogenesis and growth by N-RAS and VEGF, Cell
Cycle 11 (2012) 21372145.
[107] H.R. Kim, J.S. Roe, J.E. Lee, I.Y. Hwang, E.J. Cho, H.D. Youn, A p53-inducible
microRNA-34a downregulates Ras signaling by targeting IMPDH, Biochem.
Biophys. Res. Commun. 418 (2012) 682688.
[108] X. Yang, X. Lin, X. Zhong, S. Kaur, N. Li, S. Liang, H. Lassus, L. Wang, D. Katsaros, K.
Montone, X. Zhao, Y. Zhang, R. Butzow, G. Coukos, L. Zhang, Double-negative feedback
loop between reprogramming factor LIN28 and microRNA let-7 regulates aldehyde
dehydrogenase 1-positive cancer stem cells, Cancer Res. 70 (2010) 94639472.
[109] B. Kefas, L. Comeau, N. Erdle, E. Montgomery, S. Amos, B. Purow, Pyruvate kinase
M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells, Neuro Oncol. 12 (2010) 11021112.
[110] V. Aumiller, K. Frstemann, Roles of microRNAs beyond developmentmetabolism and neural plasticity, Biochim. Biophys. Acta. 1779 (2008) 692696.
[111] M. Mutallip, N. Nohata, T. Hanazawa, N. Kikkawa, S. Horiguchi, L. Fujimura, K.
Kawakami, T. Chiyomaru, H. Enokida, M. Nakagawa, Y. Okamoto, N. Seki, Glutathione S-transferase P1 (GSTP1) suppresses cell apoptosis and its regulation by
miR-133alpha in head and neck squamous cell carcinoma (HNSCC), Int. J. Mol.
Med. 27 (2011) 345352.

[112] R. Fang, T. Xiao, Z. Fang, Y. Sun, F. Li, Y. Gao, Y. Feng, L. Li, Y. Wang, X. Liu, H. Chen,
X.Y. Liu, H. Ji, MicroRNA-143 (miR-143) regulates cancer glycolysis via targeting
hexokinase 2 gene, J. Biol. Chem. 287 (2012) 2322723235.
[113] L.H. Gregersen, A. Jacobsen, L.B. Frankel, J. Wen, A. Krogh, A.H. Lund, microRNA-143
down-regulates hexokinase 2 in colon cancer cells, BMC Cancer 12 (2012) 232.
[114] M. Kaller, S.T. Liffers, S. Oeljeklaus, K. Kuhlmann, S. Roh, R. Hoffmann, B.
Warscheid, H. Hermeking, Genome-wide characterization of miR-34a induced
changes in protein and mRNA expression by a combined pulsed SILAC and microarray analysis, Mol. Cell. Proteomics 10 (2011) M111M10462.
[115] J. Cheng, J.M. Guo, B.X. Xiao, Y. Miao, Z. Jiang, H. Zhou, Q.N. Li, piRNA, the new
non-coding RNA, is aberrantly expressed in human cancer cells, Clin. Chim.
Acta 412 (2011) 16211625.
[116] S. Siddiqi, I. Matushansky, Piwis and piwi-interacting RNAs in the epigenetics of
cancer, J. Cell. Biochem. 113 (2012) 373380.
[117] Y. Ye, D.T. Yin, L. Chen, Q. Zhou, R. Shen, G. He, Q. Yan, Z. Tong, A.C. Issekutz, C.L.
Shapiro, S.H. Barsky, H. Lin, J.J. Li, J.X. Gao, Identication of Piwil2-like (PL2L)
proteins that promote tumorigenesis, PLoS One 5 (2010) e13406.
[118] S. Siddiqi, M. Terry, I. Matushansky, Hiwi mediated tumorigenesis is associated
with DNA hypermethylation, PLoS One 7 (2012) e33711.
[119] D.T. Yin, Q. Wang, L. Chen, M.Y. Liu, C. Han, Q. Yan, R. Shen, G. He, W. Duan, J.J. Li,
A. Wani, J.X. Gao, Germline stem cell gene PIWIL2 mediates DNA repair through
relaxation of chromatin, PLoS One 6 (2011) e27154.
[120] N. Goda, M. Kanai, Hypoxia-inducible factors and their roles in energy metabolism, Int. J. Hematol. 95 (2012) 457463.
[121] W. Zhou, M. Choi, D. Margineantu, L. Margaretha, J. Hesson, C. Cavanaugh, C.A.
Blau, M.S. Horwitz, D. Hockenbery, C. Ware, H. Ruohola-Baker, HIF1alpha induced switch from bivalent to exclusively glycolytic metabolism during
ESC-to-EpiSC/hESC transition, EMBO J. 31 (2012) 21032116.
[122] Y. Ma, D. Liang, J. Liu, K. Axcrona, G. Kvalheim, T. Stokke, J.M. Nesland, Z. Suo,
Prostate cancer cell lines under hypoxia exhibit greater stem-like properties,
PLoS One 6 (2011) e29170.
[123] D. Liang, Y. Ma, J. Liu, C.G. Trope, R. Holm, J.M. Nesland, Z. Suo, The hypoxic microenvironment upgrades stem-like properties of ovarian cancer cells, BMC
Cancer 12 (2012) 201.
[124] C. Sun, H. Song, H. Zhang, C. Hou, T. Zhai, L. Huang, L. Zhang, CD133 expression in
renal cell carcinoma (RCC) is correlated with nuclear hypoxia-inducing factor
1alpha (HIF-1alpha), J. Cancer Res. Clin. Oncol. 138 (2012) 16191624.
[125] P. Icard, H. Lincet, A global view of the biochemical pathways involved in the
regulation of the metabolism of cancer cells, Biochim. Biophys. Acta. 1826
(2012) 423433.
[126] E.A. Mazzio, N. Boukli, N. Rivera, K.F. Soliman, Pericellular pH homeostasis is a
primary function of the Warburg effect: inversion of metabolic systems to control lactate steady state in tumor cells, Cancer Sci. 103 (2012) 422432.
[127] N. Sen, Y.K. Satija, S. Das, p53 and metabolism: old player in a new game, Transcription 3 (2012) 119123.
[128] S.L. Habib, A. Yadav, L. Mahimainathan, A.J. Valente, Regulation of PI 3-K, PTEN,
p53, and mTOR in malignant and benign tumors decient in tuberin, Genes Cancer 2 (2011) 10511060.
[129] J.Q. Chen, J. Russo, Dysregulation of glucose transport, glycolysis, TCA cycle and
glutaminolysis by oncogenes and tumor suppressors in cancer cells, Biochim
Biophys Acta. 1826 (2012) 370384.
[130] M.S. Song, L. Salmena, P.P. Pandol, The functions and regulation of the PTEN tumour suppressor, Nat. Rev. Mol. Cell Biol. 13 (2012) 283296.
[131] I. Garcia-Cao, M.S. Song, R.M. Hobbs, G. Laurent, C. Giorgi, V.C. de Boer, D.
Anastasiou, K. Ito, A.T. Sasaki, L. Rameh, A. Carracedo, H.M. Vander, L.C.
Cantley, P. Pinton, M.C. Haigis, P.P. Pandol, Systemic elevation of PTEN induces
a tumor-suppressive metabolic state, Cell 149 (2012) 4962.
[132] J. Liu, Z. Feng, PTEN, energy metabolism and tumor suppression, Acta Biochim.
Biophys. Sin. (Shanghai) 44 (2012) 629631.
[133] A. Krzeslak, Akt kinase: a key regulator of metabolism and progression of tumors, Postepy Hig. Med. Dosw. (Online) 64 (2010) 490503.
[134] D.J. Mulholland, N. Kobayashi, M. Ruscetti, A. Zhi, L.M. Tran, J. Huang, M. Gleave,
H. Wu, Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells, Cancer Res. 72
(2012) 18781889.
[135] M. Sebbagh, S. Olschwang, M.J. Santoni, J.P. Borg, The LKB1 complex-AMPK pathway: the tree that hides the forest, Fam. Cancer 10 (2011) 415424.
[136] A.S. Green, N. Chapuis, C. Lacombe, P. Mayeux, D. Bouscary, J. Tamburini,
LKB1/AMPK/mTOR signaling pathway in hematological malignancies: from metabolism to cancer cell biology, Cell Cycle 10 (2011) 21152120.
[137] J.I. Partanen, T.A. Tervonen, M. Myllynen, E. Lind, M. Imai, P. Katajisto, G.J.
Dijkgraaf, P.E. Kovanen, T.P. Makela, Z. Werb, J. Klefstrom, Tumor suppressor
function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity,
Proc. Natl. Acad. Sci. U. S. A. 109 (2012) E388E397.
[138] B.Y. Shorning, A.R. Clarke, LKB1 loss of function studied in vivo, FEBS Lett. 585
(2011) 958966.
[139] S. Gurumurthy, S.Z. Xie, B. Alagesan, J. Kim, R.Z. Yusuf, B. Saez, A. Tzatsos, F.
Ozsolak, P. Milos, F. Ferrari, P.J. Park, O.S. Shirihai, D.T. Scadden, N. Bardeesy,
The Lkb1 metabolic sensor maintains haematopoietic stem cell survival, Nature
468 (2010) 659663.
[140] Y. Gu, S. Lin, J.L. Li, H. Nakagawa, Z. Chen, B. Jin, L. Tian, D.A. Ucar, H. Shen, J. Lu,
S.N. Hochwald, F.J. Kaye, L. Wu, Altered LKB1/CREB-regulated transcription
[141]
[142]
[143]
[144]
[145]
[146]
[147]
[148]
[149]
[150]
[151]
[152]
[153]
[154]
[155]
[156]
[157]
[158]
[159]
[160]
[161]
[162]
[163]
[164]
[165]
[166]
[167]
[168]
[169]
[170]
59
co-activator (CRTC) signaling axis promotes esophageal cancer cell migration

and invasion, Oncogene 31 (2012) 469479.
K. Linher-Melville, S. Zantinge, G. Singh, Liver kinase B1 expression (LKB1) is repressed by estrogen receptor alpha (ERalpha) in MCF-7 human breast cancer
cells, Biochem. Biophys. Res. Commun. 417 (2012) 10631068.
E.R. Kline, S. Muller, L. Pan, M. Tighiouart, Z.G. Chen, A.I. Marcus, Localization-specic
LKB1 loss in head and neck squamous cell carcinoma metastasis, Head Neck 33
(2011) 15011512.
M. Sanchez-Cespedes, The role of LKB1 in lung cancer, Fam. Cancer 10 (2011)
447453.
J.L. Herrmann, Y. Byekova, C.A. Elmets, M. Athar, Liver kinase B1 (LKB1) in the
pathogenesis of epithelial cancers, Cancer Lett. 306 (2011) 19.
Y. Gao, G. Ge, H. Ji, LKB1 in lung cancerigenesis: a serine/threonine kinase as
tumor suppressor, Protein Cell 2 (2011) 99107.
R.F. de Wilde, N.A. Ottenhof, M. Jansen, F.H. Morsink, W.W. de Leng, G.J.
Offerhaus, L.A. Brosens, Analysis of LKB1 mutations and other molecular alterations in pancreatic acinar cell carcinoma, Mod. Pathol. 24 (2011) 12291236.
Y. Gao, Q. Xiao, H. Ma, L. Li, J. Liu, Y. Feng, Z. Fang, J. Wu, X. Han, J. Zhang, Y. Sun,
G. Wu, R. Padera, H. Chen, K.K. Wong, G. Ge, H. Ji, LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling, Proc. Natl.
Acad. Sci. U. S. A. 107 (2010) 1889218897.
D. Carling, C. Thornton, A. Woods, M.J. Sanders, AMP-activated protein kinase:
new regulation, new roles? Biochem. J. 445 (2012) 1127.
R.U. Svensson, R.J. Shaw, Cancer metabolism: tumour friend or foe, Nature 485
(2012) 590591.
S.M. Jeon, N.S. Chandel, N. Hay, AMPK regulates NADPH homeostasis to promote
tumour cell survival during energy stress, Nature 485 (2012) 661665.
K. Inoki, J. Kim, K.L. Guan, AMPK and mTOR in cellular energy homeostasis and
drug targets, Annu. Rev. Pharmacol. Toxicol. 52 (2012) 381400.
D.G. Hardie, AMP-activated protein kinase: an energy sensor that regulates all
aspects of cell function, Genes Dev. 25 (2011) 18951908.
B. Xiao, M.J. Sanders, E. Underwood, R. Heath, F.V. Mayer, D. Carmena, C. Jing,
P.A. Walker, J.F. Eccleston, L.F. Haire, P. Saiu, S.A. Howell, R. Aasland, S.R.
Martin, D. Carling, S.J. Gamblin, Structure of mammalian AMPK and its regulation by ADP, Nature 472 (2011) 230233.
B. Krock, N. Skuli, M.C. Simon, The tumor suppressor LKB1 emerges as a critical
factor in hematopoietic stem cell biology, Cell Metab. 13 (2011) 810.
B.M. Andrade, J.M. Cazarin, P. Zancan, D.M.D. Carvalho, Amp-activated protein
kinase up regulates glucose uptake in thyroid pccl3 cells independent of thyrotropin, Thyroid 22 (2012) 10631068.
E. Vakana, L.C. Platanias, AMPK in BCR-ABL expressing leukemias. Regulatory effects and therapeutic implications, Oncotarget 2 (2011) 13221328.
E. Vakana, J.K. Altman, H. Glaser, N.J. Donato, L.C. Platanias, Antileukemic effects
of AMPK activators on BCR-ABL-expressing cells, Blood 118 (2011) 63996402.
W. Mair, I. Morantte, A.P. Rodrigues, G. Manning, M. Montminy, R.J. Shaw, A.
Dillin, Lifespan extension induced by AMPK and calcineurin is mediated by
CRTC-1 and CREB, Nature 470 (2011) 404408.
W.N. William, J.S. Kim, D.D. Liu, L. Solis, C. Behrens, J.J. Lee, S.M. Lippman, E.S. Kim,
W.K. Hong, I.I. Wistuba, H.Y. Lee, The impact of phosphorylated AMP-activated protein kinase expression on lung cancer survival, Ann. Oncol. 23 (2012) 7885.
C.W. Lee, L.L. Wong, E.Y. Tse, H.F. Liu, V.Y. Leong, J.M. Lee, D.G. Hardie, I.O. Ng,
Y.P. Ching, AMPK promotes p53 acetylation via phosphorylation and inactivation of SIRT1 in liver cancer cells, Cancer Res. 72 (2012) 43944404.
I. Martinez-Reyes, M. Sanchez-Arago, J.M. Cuezva, AMPK and GCN2-ATF4 signal the
repression of mitochondria in colon cancer cells, Biochem. J. 444 (2012) 249259.
Y.H. Kim, H. Liang, X. Liu, J.S. Lee, J.Y. Cho, J.H. Cheong, H. Kim, M. Li, T.J. Downey, M.D.
Dyer, Y. Sun, J. Sun, E.M. Beasley, H.C. Chung, S.H. Noh, J.N. Weinstein, C.G. Liu, G.
Powis, AMPKalpha modulation in cancer progression: multilayer integrative analysis
of the whole transcriptome in Asian gastric cancer, Cancer Res. 72 (2012) 25122521.
W.H. Tong, C. Sourbier, G. Kovtunovych, S.Y. Jeong, M. Vira, M. Ghosh, V.V. Romero, R.
Sougrat, S. Vaulont, B. Viollet, Y.S. Kim, S. Lee, J. Trepel, R. Srinivasan, G. Bratslavsky, Y.
Yang, W.M. Linehan, T.A. Rouault, The glycolytic shift in fumarate-hydratase-decient
kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular
iron levels, Cancer Cell 20 (2011) 315327.
A.C. Buckendahl, J. Budczies, O. Fiehn, S. Darb-Esfahani, T. Kind, A. Noske, W. Weichert,
J. Sehouli, E. Braicu, M. Dietel, C. Denkert, Prognostic impact of AMP-activated protein
kinase expression in ovarian carcinoma: correlation of protein expression and
GC/TOF-MS-based metabolomics, Oncol. Rep. 25 (2011) 10051012.
S. Fogarty, D.G. Hardie, Development of protein kinase activators: AMPK as a target
in metabolic disorders and cancer, Biochim. Biophys. Acta. 1804 (2010) 581591.
D.G. Hardie, Adenosine monophosphate-activated protein kinase: a central regulator of metabolism with roles in diabetes, cancer, and viral infection, Cold
Spring Harb. Symp. Quant. Biol. 76 (2011) 155164.
D.G. Hardie, AMP-activated protein kinase: a cellular energy sensor with a key
role in metabolic disorders and in cancer, Biochem. Soc. Trans. 39 (2011) 113.
S. Becker, L. Dossus, R. Kaaks, Obesity related hyperinsulinaemia and hyperglycaemia
and cancer development, Arch. Physiol. Biochem. 115 (2009) 8696.
D. Li, Metformin as an antitumor agent in cancer prevention and treatment, J. Diabetes 3 (2011) 320327.
A. Vazquez-Martin, C. Oliveras-Ferraros, S. Cu, B. Martin-Castillo, J.A.
Menendez, Metformin and energy metabolism in breast cancer: from insulin
physiology to tumour-initiating stem cells, Curr. Mol. Med. 10 (2010) 674691.

Review Mistery of Cancer 2013

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Review Mistery of Cancer 2013

Загружено:

Авторское право:

Доступные форматы

Biochimica et Biophysica Acta 1836 (2013) 4959

Contents lists available at SciVerse ScienceDirect

Biochimica et Biophysica Acta

Unraveling the mystery of cancer metabolism in the genesis of

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

the critical role of the loss of metabolic YinYang regulatory balance in

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

2.2. Pyruvate kinase M2

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

Role in cancer metabolism

Genesis of tumor-initiating cells (TICs) and

Promotes glycolysis and glutamine, proline, glycine,

RAS (KRAS, HRAS, NRAS)

Activate glycolysis as well as glutamine,

Triggers oncogenic metabolic reprogramming,

Stimulates glycolysis as well as energy and

Triggers glycine and pyrimidine metabolism as well

Causes defective aldehyde metabolism

Inhibits histone demethylation, leading to

Increases cell stemness and promotes stem cell

regulatory element-binding protein genes (SREBP1 and SREBP2), and

3.2. Oncogenic metabolic reprogramming of the glutaminolytic pathway

3.1.5. BCR-Abl and ALDH2

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

sufcient energy and bio-materials through glutaminolysis for their

5-hydroxylmethylcytosine, resulting in genome-wide histone and

4.3. Kynurenine (Kyn)

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

5. The potential role of non-coding RNA in oncogenic metabolic

a YinYang balance. Intrinsic and extrinsic oncogenic factors may cause

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

oncogenic metabolic reprogramming and genesis of TICs need to be

silencing of p53 expression leads to metabolic reprogramming and

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

6.2.3. LKB1 and AMPK

knots of oncogenic metabolic pathways and networks, (3) studying the

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

[65] F. Morrish, J. Noonan, C. Perez-Olsen, P.R. Gafken, M. Fitzgibbon, J. Kelleher, M.

G. Zhang et al. / Biochimica et Biophysica Acta 1836 (2013) 4959

co-activator (CRTC) signaling axis promotes esophageal cancer cell migration

Вам также может понравиться