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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 . . . . . . . . . . . . . . . . . . . . . . . .

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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

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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].

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

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,

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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

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

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

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

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

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

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

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

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.

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

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).
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