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Arch. Pharm. Res.

DOI 10.1007/s12272-015-0550-6

REVIEW

ROS and energy metabolism in cancer cells: alliance for fast


growth
Sang Won Kang Sunmi Lee Eun Kyung Lee

Received: 2 November 2014 / Accepted: 5 January 2015


The Pharmaceutical Society of Korea 2015

Abstract In normal cells, the cellular reactive oxygen can be generated by either mitochondrial electron leakage
species (ROS) level is proportional to the activity of or NADPH oxidases (NOX) (Fig. 1). The free electrons
mitochondrial electron transport and tightly controlled by that are leaked from mitochondrial electron transport chain
endogenous antioxidant system. However, energy metab- reduces the dissolved oxygen to the superoxide anion,
olism and ROS homeostasis in cancer cells are much dif- similar to the Fenton reaction. The extent of mitochondrial
ferent from those in normal cells. For example, a majority electron leakage is proportional to the usability of the
of cellular glucose is metabolized through aerobic glycol- electron transport chain depending on NADH/FADH2
ysis (Warburg effect) and the pentose phosphate path- concentration in normal cells (Wang et al. 2008). In con-
way. Cancer cells harbor functional mitochondria, but trast, NOX directly produces the superoxide anion by
many mutations in nuclear DNA-encoded mitochondrial reduction of the molecular oxygen using the NADPH-
genes and mitochondrial genome result in the mitochon- derived electrons (Bedard and Krause 2007). The super-
drial metabolic reprogramming. The other characteristic of oxide anion can be converted to H2O2 by another free
cancer cells is to maintain much higher ROS level than electron or by a superoxide dismutase (SOD)-catalyzed
normal cells. Ironically, cancer cells overexpress the ROS- reaction. Conversion of H2O2 to a hydroxyl radical is
producing NADPH oxidase and the ROS-eliminating detrimental to the cells because the radical is the most
antioxidant enzymes, both of which enzyme systems share reactive among ROS and hence attacks cellular macro-
NADPH as a reducing power source. In this article, we molecules, including proteins, DNAs, and membrane lip-
review the complex connection between ROS and energy ids. The irreversible chemical modification of protein by
metabolisms in cancer cells. the hydroxyl radicals involves cross-linking and aggrega-
tion (Guptasarma et al. 1992). Unlike the hydroxyl radicals,
Keywords Reactive oxygen species  Energy the superoxide anion and hydrogen peroxide are mild
metabolism  Antioxidant enzyme  NADPH oxidase chemical species reversibly oxidizing proteins and DNAs.
The ROS-mediated oxidation of macromolecules can be
measured in the cells by various methods, such as the
Introduction detection of protein carbonyls and lipid peroxidation by
immunoassays (Shacter 2000). In order to prevent such
Reactive oxygen species (ROS) include the superoxide unwanted damages, aerobic cells are equipped with a set of
anion (O2-), hydrogen peroxide (H2O2), and hydroxyl peroxidase enzymes, including peroxiredoxin (Prx), gluta-
radical (OH). Among these species, the superoxide anion thione peroxidase (Gpx), and catalase, that reduce hydro-
gen peroxide to water (Fig. 2). Hence, a broad distribution
of the peroxidase enzymes is an evolutionary advantageous
S. W. Kang (&)  S. Lee  E. K. Lee strategy for aerobic cells to prevent the formation of
Department of Life Sciences, Research Center for Cell
hydroxyl radicals throughout cellular compartments. Like
Homeostasis, Ewha Womans University, Seoul 120-750,
Republic of Korea NOX enzymes, the reducing power for the activity of the
e-mail: kangsw@ewha.ac.kr peroxidase enzymes also comes from NADPH. Thus, the

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S. W. Kang et al.

2e-

2e - Leakage

e- e- e-

Fig. 1 Cellular ROS hemeostasis. Free unpaired electrons are leaked membrane, mitochondria, and nucleus. The superoxide anion is then
while the two electrons liberated from NADH are transported along converted to the hydrogen peroxide spontaneously or by superoxide
the mitochondrial electron transport chain and react with the dismutase. Before its conversion to hydroxyl radicals, H2O2 is
molecular oxygen to produce the superoxide anion. Alternatively, reduced to water by cellular antioxidant peroxidases (peroxiredoxin
the superoxide anions can be produced by the catalytic activity of and glutathione peroxidase) in use of NADPH-driven electrons
NADPH oxidases in many different locations, including plasma

Fig. 2 Reaction mechanism of


peroxidase enzymes. Gpx1
Glutathione peroxidase (Gpx) Gpx2 2H2O
catalyzes the reduction reaction Gpx3
of H2O2 into water using Gpx4
electrons from NADPH by GSSG NADP+
Gpx5
coupling with via glutathione
reductase (GR) and glutathione
(GSH); whereas, the
Gpx GR
peroxiredoxin (Prx) does the
same reaction using NADPH by GSH NADPH
coupling with thioredoxin
reductase (TrxR) and
thioredoxin (Trx) SOD Catalase Pentose
O2- H 2O 2 2H2O+O2 phosphate
pathway

Trxred NADP+ Malic enzyme

Prx TrxRs

Prx1 Trxox NADPH


Prx2
Prx3
Prx4
Prx5 2H2O

maintenance of ROS homeostasis exclusively relies on the glycolysis (Warburg effect) and the PPP. Cancer cell
energy metabolism, such as pentose phosphate pathway mitochondria is functional, but metabolize only *5 % of
(PPP) for the NADPH supply. It is well-established that the glucose (Vander Heiden et al. 2009). The tricarboxylic acid
cancer cell metabolism is distinct from normal cells. In (TCA) cycle is altered because of the mutation of the key
cancer cells, glucose is metabolized through aerobic enzymes, such as isocitrate dehydrogenase (IDH). Such

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ROS and energy metabolism in cancer

abnormal respiratory metabolic pathways influence energy associated PTP integrates the site-selective phosphoryla-
balance and thereby the ROS balance in cancer cells. In tion. The PTPs are well known to be redox regulated by
this review, we introduce the basic principle on the ROS- H2O2; however, the substrate specificity of PTPs remains in
mediated protein regulation and discuss the connection debate (Tonks 2006, 2005). Therefore, identification of such
between ROS and energy metabolism focusing on the a site-specific PTP toward PDGFRb may change a paradigm
redox-dependent protein regulation. on the mechanism of PTP action. In other cases, the cysteine
sulfenyl group forms mixed disulfide linkage with either a
neighboring cysteine sulfhydryl group, also known as
Oxidation-dependent regulation of signaling protein resolving cysteine (CR), or glutathione. The intramolecular
function by ROS formation of cysteine sulfenyl or disulfide linkage in a
protein is sufficient to control its activity via a structural
H2O2 can oxidize the cysteinyl thiol to the cysteinyl sulfenyl change. For example, in the case of E. coli transcription
group on proteins. The cysteinyl sulfenyl group is further factor OxyR, the reactive cysteine oxidation results in a
oxidized into the sulfenic/sulfonic acid or form disulfide structural change by the formation of intramolecular disul-
with other thiol group. The disulfide is formed intramolec- fide between two cysteine residues separated by 17 A (Choi
ularly or in a mixed disulfide. All these cysteine oxidation et al. 2001). The peroxidatic cysteine residue in the 2-Cys
processes are reversible by the activity of redox proteins, Prx enzyme with fully-folded conformation reacts with
such as sulfiredoxin and thioredoxin (Fig. 3). Such H2O2- H2O2 and then forms intramolecular disulfide with CR res-
mediated reversible oxidation of proteins was intensively idue buried 14 A away (Wood et al. 2003). Furthermore, the
studied in the receptor-mediated signal transduction. The cumulative peroxidatic reaction in the Prx enzymes causes
first pioneer work was the H2O2-mediated tyrosine phos- the hyperoxidation of the active-site cysteine residue into
phorylation in the PDGF-treated smooth muscle cells cysteine sulfinic and sulfonic acids (Yang et al. 2002). Such
(Sundaresan et al. 1995). This work opens a redox signaling hyperoxidation turns out to be reversible by sulfiredoxin in
field and makes the researchers focused on protein tyrosine an ATP-dependent manner (Jeong et al. 2006; Woo et al.
phosphatase (PTP), which has a reactive cysteine residue in 2003; Biteau et al. 2003).
active site. In PTPs, H2O2 oxidizes the thiolate group of the Recently, accumulating evidence supports the signifi-
active-site cysteine residue to the sulfenyl group, which in cant role of the cysteine oxidation in the signaling proteins.
turn forms sulfenylamide linkage by reacting with the A Src family kinase Lyn was activated by the H2O2-
peptidyl a-amino group (van Montfort et al. 2003; Salmeen dependent oxidation of a cysteine residue Cys466 (Yoo
et al. 2003). After a decade, it has been shown that Prx II is et al. 2011). A DNA damage response kinase ATM forms
an endogenous peroxidase enzyme that regulates the level of several disulfide bonds upon the H2O2 oxidation. Among
intracellular H2O2 and PDGFRb phosphorylation induced them, the Cys2991-containing intermolecular disulfide is
by PDGF (Choi et al. 2005). A new finding was that the essential for the ATM activation (Guo et al. 2010). A key
intracellular H2O2 under the control of Prx II affect the endothelial growth factor receptor VEGFR2 is oxidized at
phosphorylation of only two selective tyrosine residues on Cys1206 when endogenous Prx II is absent and subsequently
PDGFRb. This study further indicates that a membrane- inactivated by the formation of an intramolecular disulfide
linkage (Kang et al. 2011). In most cases, the importance of
the cysteine oxidation is proven by site-directed mutagen-
Cys-SOH
esis: however, there is no structural evidence showing the
+ H 2O2

molecular mechanism underlying how the cysteine oxida-


tion changes function or activity of mammalian signaling
proteins.
ATP NADPH
Cys-SO2/3H Srx Cys-SH Trx Cys-S-S-R
Connection between ROS and energy metabolism

Fig. 3 Reversible oxidation of cysteine sulfhydryl on proteins. The


The best example of ROS-dependent regulation of met-
cysteine sulfhydryl group (SH) can be ionized into thiolate anion via
deprotonation in a hydrophobic pocket and then react with H2O2. The abolic enzymes is glyceraldehyde-3-phosphate dehydro-
resulting cysteine sulfenyl group (SOH) is further oxidized to genase (GAPDH) and PKM2 (Fig. 4). GAPDH contains
sulfinic/sulfonic group (SO2/3H) or a mixed disulfide with other many free cysteine thiols including several active-site
cysteine SH, typically GSH or a neighboring resolving cysteine. The
thiols. The cysteine thiols in GAPDH can be oxidized by
cysteine sulfinic acid is reduced by sulfiredoxin (Srx) in a ATP-
dependent manner; whereas, the disulfide is reduced by thioredoxin different types of ROS, such as superoxide, H2O2, nitric
(Trx) in a NADPH-dependent manner oxide, and peroxynitrite (Rodacka et al. 2014; Hwang

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S. W. Kang et al.

Fig. 4 ROS-dependent p53


regulation of energy metabolism
in cancer cells. ATM and
AMPK are activated by the
H2O2 oxidation; whereas, two TIGAR
glycolytic enzymes, GAPDH
and PKM2, are inactivated upon
oxidation F-2,6-bisP Pyruvate
PYGL Glucose
Glycogen
n G-1-P PKM2
GAPDH
DH
H2O2 ATM G-6-P F-1,6-bisP H2O2
p53 G6PD Glycolysis
O2
NOX
TAp73/p63 Pentose
O2-
Phosphate NADPH
Pathway H2O2
Prx
Fatty acid Gpx
Starvation AMPK ACC1/2 H 2O
synthesis

H2O2 Fumarate GSH

et al. 2009; Ishii et al. 1999; Souza and Radi 1998). Such suggests the importance of glucose flux to the PPP in
GAPDH oxidation is also observed in cardiac tissues cancer cell survival. The glycogen degradation by gly-
under ischemia and reperfusion (Eaton et al. 2002). It is cogen phosphorylase was also shown to be critical for
of importance that the GAPDH oxidation reroutes the reducing ROS level via PPP, thereby preventing tumor-
carbohydrate flux from glycolysis to the PPP, which igenesis (Favaro et al. 2012). A prospective conclusion is
results in the reduced oxidative stress (Ralser et al. that the ROS-dependent regulation of energy metabolism
2007). Given the additional signaling function of GAP- drives the carbohydrate flux to PPP, thereby increasing
DH beyond glycolysis (Morigasaki et al. 2008), the redox the NADPH level to counteract intracellular ROS.
regulation of GAPDH via the cysteine oxidation may Conversely, some metabolites can regulate the cellular
play a key role in linking the signaling to the glycolysis. redox status through ROS-metabolizing systems (Fig. 4).
The oxidation-dependent activation of ATM aforemen- For example, the accumulation of fumarate by the loss of
tioned can increase the activity of glucose-6-phosphate fumarate hydratase in cancer cells results in the increase of
dehydrogenase (G6PD), which is a key regulatory cellular ROS (Sullivan et al. 2013). Mechanistically, the
enzyme in the PPP, by promoting the Hsp27 phosphor- accumulated fumarate reacts with GSH to form succinated
ylation and its binding to G6PD (Cosentino et al. 2011). GSH that exhausts cellular NADPH via reaction with GSH
This also counteracts to the oxidative stress by promoting reductase. One-carbon metabolism involving serine, gly-
the NADPH-mediated antioxidant defenses. Another cine, and folate cycle is hyperactivated in tumorigenesis
exciting example is pyruvate kinase M2 (PKM2) that (Locasale 2013). Serine is also shown to be required for
catalyzes conversion of phosphoenolpyruvate to pyru- cancer cell survival: therefore, the serine starvation induces
vate. Unlike PKM1, the PKM2 is allosterically regulated the active serine biosynthesis in the cancer cells (Maddocks
by glycolytic metabolite fructose-1,6-phosphate (Chris- et al. 2013). Serine can be converted to the GSH via a
tofk et al. 2008). H2O2 inhibits the PKM2 by the cysteine trans-sulfuration pathway associated with methionine
oxidation and such inhibition changes the glucose flux cycle, thereby maintaining cellular antioxidant defense. A
into the PPP that generates sufficient NADPH to elimi- recent quantitative analysis of NADPH flux indicates that
nate ROS (Anastasiou et al. 2011). Vaughn et al. showed serine-driven one-carbon metabolism including the oxida-
that the oxidized cytochrome c is pro-apoptotic in cancer tion of methylene tetrahydrofolate to 10-formyl-tetrahy-
cells and the high level of the reduced glutathione (GSH) drofolate is coupled to NADP? reduction (Fan et al. 2014),
by PPP is essential for keeping the cytochrome c in which suggests a role of one-carbon metabolites in
reduced state (Vaughn and Deshmukh 2008). This result NADPH generation.

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ROS and energy metabolism in cancer

On the other hand, the cellular signaling pathways for breast and prostate cancers (Fagerholm et al. 2008; Zhang
cancer cell survival directly or indirectly link ROS to et al. 2014; Ergen et al. 2007). However, targeting mito-
metabolic pathways. One important signaling is the tumor chondrial respiratory chain for cancer prevention is at a high
suppressor p53-dependent regulation of energy metabolism risk because the mitochondrial ROS is proportionally cor-
(Fig. 4). The p53 protein directly binds to G6PD and related to the respiratory activity even in normal cells (Wang
inhibits glucose flux via PPP (Jiang et al. 2011). However, et al. 2008). Moreover, the cancer cell-specific energy
the p53 transcriptional activity lowers the level of fructose- metabolism is distinct in that the glucose flux through the
2,6-bisphosphate, an allosteric regulator of phosphofruc- PPP rather than the tricarboxylic acid cycle and the respi-
tokinase in glycolysis, through its target gene TIGAR and, ratory chain is dominant in generating the reducing power
therefore, results in a decrease of cellular ROS level NADPH in cancer cells, especially with p53 mutation
(Bensaad et al. 2006). The p53-related protein TAp73 (Vander Heiden et al. 2009). The worst scenario is that
inversely induces G6PD expression and enhances the PPP NADPH is used for both ROS production and elimination
glucose flux (Jiang et al. 2013; Du et al. 2013). Another via NOX and Prx/Gpx, respectively. Hence, the ROS-based
p53-related protein TAp63a promotes the glucose flux to anti-cancer strategy must be focused on a ROS network
PPP to prevent oxidative stress in osteosarcoma cells composed of NADPH-dependent oxidases and peroxidases
(DAlessandro et al. 2014). Overall, the p53 and its related in a cell type-specific context.
proteins regulate the cellular ROS homeostasis through The first isoform of NOX family enzymes, now named as
controlling the glucose flux to PPP. The other key regulator NOX1, is a homolog of gp91phox (now NOX2 isoform) that
of metabolic stress is the AMP-dependent protein kinase induces the cell transformation (Arnold et al. 2001; Suh
(AMPK) that plays an important role in NADPH homeo- et al. 1999). The NOX family consists of 7 members, such as
stasis. AMPK is shown to be induced by low oxygen and NOX1 thru NOX5 and DUOX1/2. Among the family
glucose starvation similar to the tumor condition (Ladero- members, NOX1 and NOX4 are well-documented related to
ute et al. 2006) and confers a tolerance to cancer cells the cancer biology (Bonner and Arbiser 2012). Recent evi-
against metabolic stress (Kato et al. 2002). The underlying dence indicates a biological function of NOX enzymes in
mechanism is recently found that AMPK maintains inflammatory signaling as a partner of toll-like receptors
NADPH level by decreasing the NADPH consumption (Jeon et al. 2010; Yang et al. 2009; Park et al. 2006). Indeed,
through fatty acid biosynthesis by inactivating acetyl-CoA the involvement of NOX enzymes in hepatocarcinoma and
carboxylases, ACC1 and ACC2, under the condition where ulcerative colitis is frequently reported (Parzefall et al. 2014;
the pentose phosphate pathway is impaired (Jeon et al. Crosas-Molist et al. 2014; Treton et al. 2014). Thus, there
2012). More interesting report was that the AMPK can be are much efforts on developing a NOX-targeting agent for
activated by H2O2-dependent oxidation in the cysteine anti-cancer strategy. On the other hand, the expressional
residues (Zmijewski et al. 2010). This is the only evidence alteration of peroxidase enzymes is also observed in various
but it implicates a link between ROS and energy balance. cancer types (Lubos et al. 2011; Kang et al. 2005). Since
GPx enzymes are selenium-containing proteins, a correla-
tion between low selenium diet and cancer risk may involve
Targeting ROS-dependent energy metabolism the GPx-1 activity. Moreover, the GPx-1 expression is
for cancer prevention reduced in many cancer types (Cullen et al. 2003; Gladyshev
et al. 1998) and is associated with the DNA damage-related
Based on the fact that the cancer cells produce more ROS tumorigenesis (Baliga et al. 2007). In contrast, the Prx
than the normal cells, there have been many trials for the enzymes are highly expressed in most cancer cells (Chae
ROS-based cancer therapy (Trachootham et al. 2009). et al. 1999; Kang et al. 2005). More importantly, the Prx1
Examples include the agents that intracellularly produce and Prx2 regulate the tyrosine phosphorylation induced by
ROS or target the antioxidant systems, such as SOD and growth factors, such as the platelet-derived growth factor
GSH. However, there is no case of an SOD or GSH treat- (PDGF) and epidermal growth factor (EGF), in cell types
ment that reduces cancer. The global level of intracellular such as primary fibroblast and vascular smooth muscle cells
ROS in cancer cells is definitely dependent on the mito- (Woo et al. 2010; Choi et al. 2005). Prx2 also protects the
chondrial source (Newmeyer and Ferguson-Miller 2003). VEGFR2 kinase activity against the H2O2-dependent inac-
Indeed, a genetic modification on mitochondrial respiratory tivation (Kang et al. 2011). A mitochondrial isoform Prx3
chain is often observed in various cancers and linked to the exhibits an anti-apoptotic function in cancer cells treated
increased cellular ROS level (Wallace 2012). In addition, with tumor necrosis factor-a and staurosporine (Chang et al.
the polymorphism of mitochondrial genes, for example, 2004). Such experimental evidence suggests that the Prx
NQO1, also accompanies with the elevated ROS level and enzymes are likely to function as a signal regulator in cancer
can be a prognostic risk factor in various cancers including cells. Recently, the first chemical inhibitor called

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adenanthin, a diterpenoid isolated from the leaves of Rab- Bensaad, K., A. Tsuruta, M.A. Selak, M.N. Vidal, K. Nakano, R.
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2012). Although it is shown later to generally target the reduction of cysteine-sulphinic acid by S. cerevisiae sulphire-
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2004. Peroxiredoxin III, a mitochondrion-specific peroxidase,
Since the mitochondrial electron transport chain is a major regulates apoptotic signaling by mitochondria. Journal of
Biological Chemistry 279(40): 4197541984.
ROS production site, its contribution to the intracellular Choi, H., S. Kim, P. Mukhopadhyay, S. Cho, J. Woo, G. Storz, and
ROS level may depend on the metabolic flux into TCA and S.E. Ryu. 2001. Structural basis of the redox switch in the OxyR
b-oxidation in cancer cells. The expression of NOX transcription factor. Cell 105(1): 103113.
enzymes is another critical ROS producer because these Choi, M.H., I.K. Lee, G.W. Kim, B.U. Kim, Y.H. Han, D.Y. Yu, H.S.
Park, et al. 2005. Regulation of PDGF signalling and vascular
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in cancer cells. Such cellular ROS level is then counteracted Christofk, H.R., M.G. Vander Heiden, N. Wu, J.M. Asara, and L.C.
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Cosentino, C., D. Grieco, and V. Costanzo. 2011. ATM activates the
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Acknowledgments This study was supported by a Grant from the Cullen, J.J., F.A. Mitros, and L.W. Oberley. 2003. Expression of
National R&D Program for Cancer Control, Ministry of Health and antioxidant enzymes in diseases of the human pancreas: Another
Welfare, Republic of Korea (1420280), the National Research Founda- link between chronic pancreatitis and pancreatic cancer. Pan-
tion Grants (2014R1A2A1A01006934 & 2012M3A9C5048709), and the creas 26(1): 2327.
Research Center for Cellular Homeostasis (2012R1A5A1048236) fun- DAlessandro, A., I. Amelio, C.R. Berkers, A. Antonov, K.H.
ded by the Korean government (MSIP). Vousden, G. Melino, and L. Zolla. 2014. Metabolic effect of
TAp63alpha: Enhanced glycolysis and pentose phosphate path-
Conflict of interest None declared. way, resulting in increased antioxidant defense. Oncotarget
5(17): 77227733.
Du, W., P. Jiang, A. Mancuso, A. Stonestrom, M.D. Brewer, A.J.
Minn, T.W. Mak, M. Wu, and X. Yang. 2013. TAp73 enhances
the pentose phosphate pathway and supports cell proliferation.
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