Metabolic Alterations in Cancer Cells

Chinese Journal of Cancer
Review
Naima Hammoudi1,2, Kausar Begam Riaz Ahmed1,2, Celia GarciaPrieto3 and Peng Huang1,2
Abstract
Cancer metabolism has emerged as an important area of research in recent years. Elucidation of the
metabolic differences between cancer and normal cells and the underlying mechanisms will not only
advance our understanding of fundamental cancer cell biology but also provide an important basis for the
development of new therapeutic strategies and novel compounds to selectively eliminate cancer cells by
targeting their unique metabolism. This article reviews several important metabolic alterations in cancer
cells, with an emphasis on increased aerobic glycolysis (the Warburg effect) and glutamine addiction, and
discusses the mechanisms that may contribute to such metabolic changes. In addition, metabolic
alterations in cancer stem cells, mitochondrial metabolism and its influence on drug sensitivity, and
potential therapeutic strategies and agents that target cancer metabolism are also discussed.
Key words Cancer metabolism, the Warburg effect, mitochondria, glycolysis, glutamine, cancer stem cells
Cancer cells have long been known to exhibit

profound alterations in their metabolism, as exemplified
by the Warburg effect, a phenomenon of cancer cells
with elevated aerobic glycolysis[13]. Reprogramming of
the cellular energy metabolism constitutes an emerging
hallmark of cancer and may serve as a biochemical
basis for new therapeutic intervention[4]. Tremendous
efforts in recent years have been devoted to unveiling
the underlying mechanisms for metabolic alterations in
cancer, thus triggering considerable research interest in
mitochondria, bioenergetics, and redox regulation in
normal and malignant cells. Both glucose and glutamine
are key metabolic substrates in cancer cells and are
critical for cancer development, invasion, and metastases
[59]
. Glutamine is an abundant amino acid in human
plasma and is present at high concentrations in the
cell culture. Several oncogenes,
medium used for
1
Department of Molecular Pathology, The University
of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
2
The University of Texas Graduate School of Biomedical Sciences at
Houston, Houston, Texas 77030, USA; 3The Department of Health
Disparities Research, The University of Texas MD Anderson Cancer
Center, Houston, Texas 77030, USA.
Peng Huang, Department of Molecular

Pathology, The University of Texas MD Anderson Cancer Center, 1515
Holcombe Boulevard, Houston, TX 77030, USA. Tel: +17138346044;
Fax: 7138346084; Email: phuang@mdanderson.org.
10.5732/cjc.011.10267
508 www.cjcsysu.com
including c
and
, have been identified to
promote the expression of metabolic enzymes and
regulators that lead to preferential use of glycolysis over
mitochondrial oxidative phosphorylation (OXPHOS). Loss
of tumor suppressors, such as p53, fumarate hydratase
(FH), and succinate dehydrogenase (SDH), also results
in significant changes in energy metabolism and may
contribute to activation of hypoxiainducible factor (HIF)
1dependent
pathways and adaptation to tumor
hypoxia[10,11].
Mitochondria are critical cellular organelles in
which many key metabolic pathways converge. Whether
metabolic alterations drive tumorigenesis or are a
consequence of malignant transformation is still a matter
of debate. Mitochondrial dysfunction has been directly
linked to alterations in gene expression profiles and
significantly affects cancer development. An impaired
mitochondrial respiratory chain (MRC) may significantly
alter the expression of important genes such as forkhead
box O family (
) and apoptosis signalregulating
kinase 1 (
), leading to changes in cell cycle
progression[12]. Mutations in mitochondrial DNA and nuclear
DNAencoded genes can also modulate cancer cell
metabolism. Aberrant expression of specific molecules
such as the serine/threonine protein kinase AKT and the
mammalian target of rapamycin (mTOR) promotes
increased glucose metabolism in cancer cells. In fact,
AKT alone is sufficient to produce a glycolytic phenotype
and glucose dependence in cancers[ 13 ]. Furthermore,
CACA Chinese
Anti Cancer A ssociation
Naima Hammoudi et al.
mTOR, a downstream target of AKT, seems to function

as an energy sensor that is sensitive to alterations in
nutrients and amino acids[1416] and is deregulated in many
cancer types[17]. The tumor suppressor AMPactivated
protein kinase (AMPK) is activated in response to stress
signals, such as hypoxia and low cellular ATP levels,
and regulates various critical cellular processes,
including proliferation, cell cycle progression, autophagy,
and cellular senescence, through its effects on key
molecules such as mTORC1, p53, p27, FOXO3, and
others[18,19]. In addition, metabolic reprogramming is linked
to oncogenes such as
and
and tumor
suppressors such as
that are important players in
mediating energetic pathways[2022]. A high dependency on
glycolysis in cancers is also associated with altered
glucose transporters and glycolytic enzymes such as
hexokinase II (HKII) and lactate dehydrogenase (LDH)[23,24].
Therefore, many of these key molecules that are critical
for maintaining cancer metabolism may be considered
as potential targets for metabolic intervention in cancer
treatment. The following sections provide an overview of
several key metabolic alterations in cancers, their potential
links to oncogenes and tumor suppressors, and the
biochemical and molecular basis for targeting altered
metabolism in cancers.
Metabolic Alterations in Cancers

Glycolysis and the Warburg effect
Warburg observed in early 1920s that tumor cells
exhibited significant alterations in energy metabolism and
mitochondrial respiration compared to normal cells[2,25].
He showed that cancer cells actively used glycolysis for
ATP generation, even in the presence of an abundant
supply of oxygen, a phenomenon known as the Warburg
effect[1,25]. Warburg further postulated that the metabolic
shift from OXPHOS to glycolysis in neoplastic cells might
be due to a respiratory injury (mitochondrial dysfunction)
leading to increased aerobic fermentation, a critical event
that was considered as the origin of cancer cells [1].
Although
whether
metabolic
alterations
drive
tumorigenesis or are an effect of transformation is still
under debate, subsequent studies showed that increased
dependence on glycolysis is observed in the majority of
tumors and that glycolysis provides ATP as well as the
metabolic intermediates essential for cancer cell
proliferation and tumor development[8,26,27].
Aerobic conversion of glucose to lactate represents a
major feature of cancer cell metabolism (Figure 1). The
high flux of glycolysis results in an increased output of
pyruvate, which may either be converted to lactate by
LDH in the cytosol or to acetylCoA by pyruvate
dehydrogenase (PDH) in the mitochondria. AcetylCoA is
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Cancer metabolism and therapeutics
further metabolized through the Kreb s cycle and the

MRC to generate ATP. The tumor hypoxic environment
,
, and
stabilize
and/or oncogenes such as
,
leading
to
upregulation
of
pyruvate
dehydrogenase kinase1 (
), in turn inactivating
and thereby preventing the conversion of pyruvate
to acetylCoA. Pyruvate is subsequently converted to
with a simultaneous oxidation of
lactate by
+
nicotinamide adenine dinucleotide (
) to
,
which is important for the glycolytic reaction at the step
catalyzed by glyceraldehyde3phosphate dehydrogenase
(
).
is upregulated not only by
but
also by other oncogenes such as
, thus ensuring
+
sufficient
is available for glycolysis in cancer cells.
The high rate of aerobic glycolysis confers several
advantages
to
cancer
cells. In
the
hypoxic
microenvironment of tumor tissues, active glycolysis
provides sufficient ATP for tumor cells when
mitochondrial OXPHOS is limited. This seems
particularly important for actively proliferating cancer
cells[1,28]. Secondly, the metabolic intermediates generated
during glycolysis provide important building blocks or
precursors for the synthesis of DNA and fatty acids and
for redox regulation[29,30]. For instance, glucose6phosphate,
the product of the first glycolytic reaction, can be
channeled to the pentose phosphate pathway (PPP) to
generate ribose5phosphate and nicotinamide adenine
dinucleotide phosphate (NADPH), which are important
for nucleic acid metabolism and redox homeostasis,
respectively.
NADPH
and
3carbon
metabolic
intermediates are also important for lipid biosynthesis.
Finally, the high levels of lactic acid produced during
glycolysis may activate metalloproteinases and matrix
remodeling enzymes, thus contributing to cancer
invasion and metastasis [29,31]. It should be noted,
however, although most cancer cells are highly active in
glycolysis, an increase in mitochondrial OXPHOS has
also been observed in some tumors.
Glutamine in cancer metabolism

Another important metabolic substrate and energy
source for tumor cells is glutamine[32]. This amino acid is
highly abundant in blood, and once it enters the cells, it
may serve as an energy source through catabolism or as
a building block via anabolism (Figure 1). In addition to
its direct involvement in metabolism, glutamine seems
able to affect amino acid transport and autophagy
through activation of mTOR complex 1 (mTORC1) [33].
Conversion of glutamine to glutamate and its channeling
into the tricarboxylic acid (TCA) cycle via ketoglutarate
induced tumor
seem essential for the oncogenic
growth in colon cancer cells[5]. Studies using tumor
xenograft models have shown that the expression of
glutaminase, an enzyme that converts glutamine to
Chin J Cancer; 2011; Vol. 30 Issue 8
509
Figure 1.
Glucose and glutamine are transported through cell membranes by their respective
transporters (GLUT 1, 3 and 4 for glucose; SLC5A1 and SLC7A1 for glutamine). Glucose is metabolized in the cytosol to pyruvate, which can
be either converted to lactate or transported into the mitochondria for further catabolism through the tricarboxylic acid (TCA) cycle coupled with
respiration through the electron transport chain (ETC). In many cancer cells, glucose is mainly used for the glycolytic pathway, leading to a
generation of lactate and important metablic intermediates such as glucose 6 phosphate for the pentose phosphate pathway (PPP) that generates
NADPH and ribose for maintaining redox balance and synthesis of nucleic acids. The flow of glucose into mitochondria in the form of pyruvate is
relatively low in cancer cells. Glutamine is actively metabolized in cancer cells, both in the cytosol and in the mitochondria, where it is catalyzed
by glutaminase to generate glutamate, which is further converted to ketoglutarate for utilization through the TCA cycle. Both glycolysis and the
TCA cycle provide important metabolic intermediates that serve as substrates for other pathways including the synthesis of nucleic acids, fatty
acids, amino acids, and glutathione. The highly active pathways in cancer cells are indicated with bold arrows, whereas the less active metabolic
flows are shown with thin arrows. Some of the important enzymes involved in cancer metabolism are indicated. HKII, hexokinase 2; PKM2,
pyruvate kinase M2 isoform; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; PDK 1, pyruvate dehydrogenase kinase 1; GLS,
glutaminase; IDH, isocitrate dehydrogenase.
glutamate, correlates with tumor growth, and that

inhibition of glutaminase in cells led to suppression of
tumorigenicity and tumor growth[7,34]. A metabolic study
using nuclear megnetic resonance (NMR) spectroscopic
analysis in glioblastoma cells cultured with isotopelabeled
glucose and glutamine demonstrated that glutamine
supplied the majority of aneplerotic carbon for the TCA
cycle in cancer cells[35]. The same study also showed that
conversion of glutamate to ketoglutarate
is the chief
source of malate, oxaloacetate, and NADPH for fatty

acid biosynthesis in tumors[35]. In fact, active glutaminolysis,
the process of glutamine catabolism, is considered as a
major metabolic feature of certain tumor cells[36,37]. Recent
studies have shown that glutamine metabolism is
510 Chin J Cancer; 2011; Vol. 30 Issue 8
regulated by the oncogene c

, which directly
stimulates the expression of the glutamine transporters
and
and indirectly promotes the
expression of glutaminase 1 (GLS1) by repressing the
[38,39]
and
.
expression of
Glutamine also contributes to the maintenance of the
antioxidant pool in cancer cells. The glutaminederived
malate from the TCA cycle serves as a substrate for
malic enzyme 1 to produce NADPH. In glioblastoma
cells, the high level of NADPH has been shown to
contribute to the active synthesis of glutathione (GSH),
which is essential for combating reactive oxygen species
(ROS)induced stress in cancer cells and maintaining
redox balance[35]. Interestingly, glutamine also seems to
play a role in cancer metastasis. Seyfried

.[6] recently
showed that inhibition of glutamine metabolism in a
mouse breast cancer model suppressed tumor
metastasis . Although suppression of the mitochondrial
glutaminase activity can inhibit oncogenic transformation[40],
the exact roles of glutamine in tumorigenesis remain to
be elucidated. The role of glutamine metabolism in
affecting tumor growth and cancer progression in
patients has not also been definitely established. Further
research is required to understand the mechanisms
underlying the glutamine addiction characteristics of
cancer cells.
Alterations of metabolic enzymes in cancers

The mitochondrial membranebound HKII has been
shown to promote the high glycolytic tumor phenotype
and to inhibit Baxinduced cytochrome mediated
apoptosis in HeLa cells[41,42]. The pyruvate kinase isoform
M2 (PKM2) seems to confer a tumorigenic advantage to
cancer cells by slowing glycolysis and channeling the
glycolytic intermediates to the PPP to produce NADPH
and other metabolic substrates[43]. Elevated levels of
PKM2 have been observed in various tumor samples[44,45],
consistent with the potential oncogenic role of this
enzyme. The cofactor NADPH not only fuels
macromolecular biosynthesis but also functions as a
major antioxidant in cells. It maintains the redox balance
during cell proliferation and is a reducing agent required
for the GSH and thioderoxin antioxidant systems that
play a major role in quenching ROS[46].
Gainoffunction mutations in isocitrate dehydro
genase I and II (
and
) have been identified in
several types of human cancers, especially in certain
gliomas and acute myelogenous leukemia[4749]. While the
wildtype
and
catalyze the conversion of
isocitrate to ketoglutarate,
mutated IDH (
,
,
) produces 2hydroxyglutarate (2HG), a
metabolite that seems to have oncogenic properties due
to its ability to affect DNA methylation[5052]. 2HG, which is
present at low concentrations in normal cells, may reach
abnormally high concentrations in glioma samples and
the serum of AML patients[49,51]. It has been reported to
decrease OXPHOS, thus potentiating the cellular
glycolysis capacity. IDH1 overexpression has been
observed in over 95% of advanced gliomas, suggesting
that it might have prognostic value in gliomas[53].
Nevertheless, further study is needed to understand why
IDH mutations have preferential distribution in certain
cancers, as well as to specifically evaluate the
mechanistic role of these mutations in cancer
development and test its value as a potential therapeutic
target.
Further, deactivating mutations in FH and SDH, first
identified in head and neck paragangliomas, have also
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been reported in hereditary leiomyomatosis, renal cell

carcinoma, and certain gastrointestinal tumors[5456]. The
succinate dehydrogenase subunit D (SDHD) protein is
one of the four subunits composing the SDH complex
(complex II). Mutations in SDHD and FH alter the
function of mitochondrial complex II, which affects the
electron flow involving flavine adenine dinucleotide
(FADH2). These mutations seem to compromise
mitochondrial respiratory function and may contribute to
the Warburg effect. Loss of FH and SDH activity leads
to accumulation of their substrates fumarate and
succinate, possibly interfering with the function of the
dioxygenases, including prolyl
ketoglutaratedependent
hydroxylases and HIF1, which catalyze a host of

biochemical reactions[11,29,57,58].
Metabolic alterations in cancer stem cells

The study of cancer stem cells, a rare subpopulation
of malignant cells with longterm selfrenewal capacity
and high tumorigenic potential, has become an important
and intensive research area in recent years. Owing to
their special biological properties, cancer stem cells are
thought to play key roles in tumor initiation, resistance to
chemotherapy and radiotherapy, and disease recurrence[59].
Although extensive information on the biological
properties of cancer stem cells, specifically with respect
to
selfrenewal,
tumorigenesis,
maintenance
of
stemness, differentiation, and regulatory mechanisms,
has been generated during the past decade, our
understanding of the metabolic properties of cancer stem
cells is rather limited. This is due in part to limited
availability of proper cancer stem cell models for
metabolic study. The low number of cancer stem cells
that can be isolated from primary tumors also limit the
scope of metabolic study in this subpopulation of cells.
Notably, certain regulatory pathways known to play
important roles in governing cell metabolism and energy
sensing have been shown to be involved in maintaining
the selfrenewal property of cancer stem cells. For
instance, the tumor suppressor
negatively
regulates the AKT pathway, thus affecting cellular uptake
blockage has been shown to
and use of glucose.
increase selfrenewal capacity and promote clonogenicity
of glioblastoma stem cells[60]. Interestingly, the tumor
suppressor
is also involved in metabolic regulation
through its effects on mitochondrial respiratory activity[22].
Inhibition of
increased the selfrenewal capacity of
glioma stem cells, whereas activation of
promoted
cell differentiation[61]. The energy censor mTOR has been
shown to play an essential role in maintaining the
hematopoietic stem cells at undifferentiated stage by
downregulating
mitochondrial
respiration[62].
The
transcription factor HIFs are often upregulated in cancer
cells and have been shown to promote the maintenance
511
of cancer stem cells in an undifferentiated state[63,64].

Interestingly, glioma stem cells seem to be confined in
the tissue niches in the brain where the oxygen
concentration is restricted[65]. Such a hypoxic
microenvironment would favor the stabilization of HIF1.
Aldehyde dehydrogenase 1 (ALDH1) is a metabolic
enzyme involved in detoxification of certain toxic
compounds and in the metabolism of biomolecules, such
as the conversion of vitamin A (retinol) to retinoic acid.
ALDH1 is often expressed in cancer stem cells and has
been used as a functional marker for isolating cancer
stem cells[66]. The retinoic acid signaling is believed to be
important in determining the cell fate. ALDH1 has been
used as a marker in detection of breast cancer stem
cells [6769] and, more recently, in lung cancer[70]. In
hematopoetic stem cells, inhibition of ALDH1 activity
leads to an increase in the population[71]. Interestingly,
the PI3K/AKT pathway seems to play a major role in
maintaining the ALDH1positive population of breast
cancer[72].
In several studies, the metabolic function in cancer
.[73]
stem cells has been directly assessed. Zhou
reported that the stemlike glioma cells with enriched
CD133+ cells showed increased tumorigenic capacity,
low mitochondrial respiration, and high glycolytic activity.
Furthermore, these metabolic properties seemed to
confer cancer stem cells the ability to survive and
proliferate in a hypoxic microenvironment and render
them highly sensitive to glycolytic inhibition[73]. Consistently,
a recent study in human pluripotent stem cells and their
differentiated counterparts showed that the stem cells
expressed high levels of glycolytic enzymes and relied
mostly on glycolysis to meet their energy demands[74]. In
hypoxiaadapted BcrAbl (+) cells that exhibited stem
celllike characteristics, the expression of glyoxalaseI,
an enzyme that detoxifies methylglyoxal (a toxic
metabolite of glycolysis) was high, and these cells were
much more sensitive to glyoxalaseI inhibitors[75]. These
studies together suggest that cancer stem cells may
have unique metabolic properties that can serve as
potential targets for anticancer therapy. As cancer stem
cells are more resistant to conventional therapeutic
agents and play a major role in therapeutic failure and
cancer recurrence, the development of novel agents that
effectively kill cancer stem cells based on their unique
metabolic properties will have major therapeutic
implications.
M etabolic Alterations and Drug Resis

tance
Defects in the mitochondrial respiration and
mutations in mitochondrial DNA (mtDNA) have been
implicated to affect drug sensitivity. Several groups have
used respirationdeficient 0 cells to investigate the role

of mitochondrial respiration in drug resistance. Singh
.[76] showed that the 0 cells were resistant to
photodynamic therapy and adriamycin but remained
Cai
sensitive to DNA alkylating agents and radiation.
.[77] reported that although staurosporine treatment

induced release of cytochrome
and activation of
caspases in both 0 and + cells, the redox homeostasis
remained unchanged in 0 cells upon induction of
apoptosis, suggesting that apoptosis and bioenergetics
are two separate events. In another study using SKHep1
hepatoma cells, deprivation of mtDNA resulted in 0
cells with elevated expression of the antioxidant enzymes
manganese superoxide dismutase and glutathione
peroxidase. These cells were relatively resistant to H2O
2
and ROSinducing agents such as doxorubicin, paraquat,
and menadione, suggesting a significant role of
mitochondrial respiration in drug sensitivity[78]. Furthermore,
respirationdefective 0 prostate cancer cells were
resistant to the cytotoxic effects of the synthetic retinoid
4HPR, implying that OXPHOS may be critical to mediate
the effects of 4HPR in transformed human prostate
cells[79]. Thus, a defect in mitochondrial respiration
function may positively or negatively impact drug
sensitivity, depending on the mechanisms of actions of
the compounds. Ironically, the mtDNAdepleted HeLa
cells (EB8 cells) lost their ability to form colonies in the
anchorageindependent colony formation assay and to
form tumors in nude mice, although both features were
restored upon introduction of normal mtDNA into the
cells[80]. It appears that a complete loss of mitochondrial
respiration may compromise the cell s ability to survive
and proliferate in the
tissue environment.
Apart from mtDNA mutations and respiratory
dysfunction, ROS and cellular redox homeostasis also
play a critical role in determining and modulating cellular
sensitivity to drugs. ROS can cause DNA mutations that
may contribute to the development of a drugresistant
phenotype. However, an increase in ROS beyond a
certain cellular threshold may lead to cell death through
various mechanisms, such as activation of the
JNK/p38mediated signaling pathway, direct damage to
the mitochondrial membrane, and release of cytochrome
[8184]
. Interestingly, malignant cells in advanced stage
cancers may develop resistance to ROS stress by
upregulation of their antioxidant capacity. For instance,
resistance to arsenic trioxide in leukemia cells has been
correlated with high cellular GSH levels and elevated
expression of superoxide dismutase 1[85,86]. Similarly,
resistance to paclitaxel and cisplatin has been
associated with increased antioxidant levels[8789]. Thus,
abrogation of the cancer cell antioxidant defense
mechanism, such as depletion of GSH using
pharmacological agents, seems to be an effective
strategy to overcome such drug resistance[90,91]. For drug
resistance associated with mitochondrial respiration

defects and increased glycolysis, the use of glycolytic
inhibitors is an effective strategy[92].
Mechanisms
Alterations
Underlying
Metabolic
After his initial observation of increased glycolysis in

cancer cells[2], Warburg later attributed this metabolic
alteration to respiratory injury and considered this as
the main cause of cancer[1]. This theory was immediately
challenged by Weinhouse, who contended that
mitochondrial respiration was functioning in cancer cells
and that active glycolysis and OXPHOS together would
result in a generation of excess ATP, thus creating a
metabolic imbalance in cancer cells[93]. More recently,
MorenoSanchez
.[94] suggested that cancer cells are
heterogeneous in their energy metabolic profiles, with
some primarily using glycolysis whereas others use
OXPHOS . Since mitochondria are the powerhouses of
the cell and serve as the converging points of multiple
metabolic pathways, mitochondrial dysfunction has long
been suspected to play a key role in metabolic
alterations in cancers. Interestingly, a recent study by
Compton
.[95] demonstrated that mitochondrial
respiratory state can profoundly affect p53 expression
and, thus, might play a role in tumorigenesis. Alterations
in cancer cell metabolism have been attributed to
dysfunctional mitochondria resulting in part from mtDNA
mutations, and metabolic reprogramming may be linked
to oncogenes and tumor suppressors that either affect
mitochondrial function or regulate important molecules
involved in the energetic pathways.
Mitochondria mutations in cancers

A major role of mitochondria is to generate energy in
the form of ATP through OXPHOS, which is carried out
through the electron transport chain (ETC) associated
with the mitochondrial inner membranes[96]. The ETC
consists of four respiratory complexes (IIV), each with
multiple protein components or subunits. Electrons are
carried through these complexes to molecular oxygen
with a simultaneous pumping of protons across the inner
membranes to generate an electrochemical gradient,
which is then used as the energy source to drive ATP
synthesis at complex V. Each ETC complex contains
subunits that are encoded by both mtDNA and nuclear
DNA, with an exception of complex II, whose subunits
are all encoded by nuclear DNA. Mammalian
mitochondria contain a genome of 16.5 kb of double
stranded circular DNA encompassing 37 genes, of which
13 are components of respiratory chain complexes[9698].
The lack of histone protection as well as the close
physical proximity of the mitochondrial genome to the
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source of ROS generation makes mtDNA highly prone to

mutations[99].
Accumulating evidence suggests that mtDNA
mutations occur at higher frequency in cancer cells than
in normal cells, perhaps due in part to the increased
ROS generation in the cancer cell mitochondria [100].
Because each cell harbors numerous mitochondria with
multiple copies of mtDNA, mutations at mtDNA can be
heteroplasmic (variably mutated mtDNA copies coexist
in the same cells) or homoplasmic (all mtDNA copies
carry the same mutations). For the heteroplasmic
mutations to have a significant effect on the cells, it is
estimated that such mutations should be predominant
and reach a minimal threshold of 60% of the
mitochondrial copies[101,102]. However, due to
selection of mutations that confer advantage for cell
survival and proliferation, the heteroplasmic mutations
with functional consequences may eventually become
homoplasmic or eliminated (disadvantage mutations).
This may explain why the majority of mutations detected
in human cancers are homoplasmic[103,104]. Figure 2 shows
a summary of mtDNA mutations in the coding region of
respiratory chain components detected in various types
of cancer tissues. Mutations can occur in any part of
mtDNA, although there may be certain hot spots
where mutations are more concentrated. Many mutations
have also been detected in the noncoding region
(Dloop), where the origin of replication and the
transcription promoter sequences are located. Mutations
of Dloop do not directly affect the structure and function
of any particular protein encoded by mtDNA but may
affect mtDNA replication and transcription.
Extensive mtDNA sequencing in breast cancer
conducted by Tan
.[105] revealed that 74% of patient
samples had mutations at 27 different sites, most of
.[106]
which were situated in the Dloop region. Parella
detected mtDNA mutations in 61% of fineneedle
aspirates of breast cancer tissues, with the majority of
mutations again located in the Dloop region. Single base
substitutions and deletions seem to be the most
common mutations found in breast cancer mtDNA. In a
.[107] reported the
colorectal cancer study, Polyak
occurrence of mutations in colon cancer cell lines as well
as the original tumors from which the cells were derived.
The mutations occurred in the coding regions including
the NADH dehydrogenase 1 (ND1), ND4L, ND5,
cytochrome , and 12S and 16S RNA genes. Mutations
in the Dloop region in colorectal cancer have also been
reported[108]. Another interesting finding was the presence
of mutations in the normal colonic crypt stem cells,
suggesting that mutations may occur before the
development of colon cancer and contribute to
carcinogenesis, although this functional role has not
been experimentally demonstrated[109]. In gastric cancer,
the Dloop region harbored mutations in 48% of the
. [110].
carcinoma samples sequen ced by Wu
513
Figure 2.
The human mitochondrial genome is a 16.5

kb double stranded circular DNA, which contains 37 genes: 13 polypeptides that are components of the electron transport complexes (ETC), 22
tRNAs, and 2 ribosomal RNAs. Mutations at the 13 ETC encoding genes may cause alterations of the respiratory chain activity and thus affect
metabolism. Each box linked to a particular mitochondrial gene region contains a partial list of mutations that have been identified in that specific
mtDNA in human cancers, with the specific cancer types indicated. The numbers represent the locations of the mutated bases (C, cytosine; G,
guanine; T, thymine; A, Adenine). Note that the two adjacent genes for ATPase6 and ATPase8 are shown in a single box.
Additionally, mtDNA mutations have been detected in

ovarian[111], hepatocellular[112,113], pancreatic[114], prostate[115],
thyroid[116], brain[117], and lung cancers[118].
Role of oncogenes and tumor suppressor genes

in alterations of cancer cell metabolism
Emerging evidence suggests that metabolic
deregulations play a crucial role in supporting cancer cell
survival, proliferation, and tumor growth and that certain
oncogenes may orchestrate the activation of enzymes
that are important for the glycolytic pathway and thus
contribute to the Warburg effect. On the other hand,
certain metabolic pathways may lead to production of
metabolites that promote silencing of tumor suppressors
and activation of certain oncogenes.

The serine/threonine kinase AKT, a downstream
effector of the insulin signaling, plays a major role in cell
survival and proliferation and is an important promoter of
glysolysis[119]. In the majority of tumor cells, Akt is
hyperactive and seems to drive addiction to glucose
metabolism for survival and proliferation [13]. The Akt
glycolytic enhancer role is driven by stimulation of
glucose uptake in response to insulin[13]. Akt upregulates
GLUT1 by enhancing its expression at transcription level.
Moreover the AKT signaling enhances glucose
metabolism within the cell by stimulating the association
of HKII with the mitochondrial outer membrane, thus
positioning
it
to
phosphorylate
glucose
to
glucose6phosphate for use in glycolysis and other

metabolic pathways [120]. Akt s ability to promote
metabolism via glycolysis is also partly due to induced
expression of glycolytic enzymes through the mTOR and
HIF1 signaling[16,121].
mTOR is an energy censor that promotes
nutrient uptake and glycolysis. Deregulation of mTOR
pathway is often found in cancer cells[17]. Under nutrient
deprivation, mTOR forms a stable complex with raptor,
leading to an inhibition of mTOR kinase activity[122]. Akt
regulates mTOR through the inactivation of the protein
tuberous sclerosis2 (TSC2). TSC2 and TSC1 associate
and form a complex that suppresses mTOR activity[123].
Activated AKT phosphorylates TSC2, thus affecting its
interaction with the small G protein Rheb, which when
loaded with GTP, activates mTORC1[122,124]. The activation
of mTORC1 increases glycolysis by increasing the
translation of the mRNA encoding HIF1 , thus
stimulating the expression of glycolytic enzymes [125].
Importantly, mTOR is regulated by liver kinase B1
(LKB1) and AMPK [126]. The mTOR energy sensor
function is conferred in part by AMPK, a heterotrimeric
serine/threonine kinase consisting of a catalytic subumit
( ) and two regulatory subunits ( and )[127]. Nutrient
depravation causes cellular stress, leading to an
increase of the AMP/ATP ratio, which promotes the
binding of AMP to the regulatory
subunit and triggers
AMPK activation [128]. AMPK activation in turn induces

TSC2 phosphorylation, leading to suppression of mTOR
activity and inhibition of protein translation. The
serine/threonine kinase LKB1 activates AMPK under low
ATP conditions[129]. Therefore, the LKB1/AMPK/mTOR
axis serves as an important energy sensor that links
energy status and the metabolic signaling pathways[130].
Hypoxia inducible factor1, a heterodimer
protein complex that consists of HIF1 and HIF1, has
been implicated in the induction of key genes involved in
cell proliferation, oxygen and nutrient delivery, and
anaerobic energy metabolism [131]. HIF1 regulation is
achieved by protein degradation of the HIF1 subunit in
response to oxygen levels in the microenvironment.
Oxygen promotes prolyl hydroxylation, which stimulates
the association of HIF1 with the von HippelLinau
(VHL) tumor suppressor, thereby targeting HIF1 for
ubiquitination and proteosomal degradation. Hypoxia
suppresses prolyl hydroxylation through a process
involving mitochondriagenerated ROS[132,133]. As such,
HIF1 is considered as the master sensor that
orchestrates cellular responses to changes in oxygen
homeostasis. In fact, HIF1 has been found to be highly
expressed within hypoxic tumors and at low levels within
normal tissue[134].
HIF1 upregulates 9 of the 10 genes involved in
glycolysis and, thus, plays a key role in switching
www.cjcsysu.com
glucose metabolism from OXPHOS to glycolysis when

cells are in a hypoxic environment[134,135]. For instance,
HIF promotes glucose uptake by upregulating the
expression of the GLUT1 and glucose metabolism by
upregulating hexokinase, the enzyme responsible for
catalyzing the first glycolytic reaction. HIF1 also
promotes the expression of LDHA at the transcription
level[136,137]. Furthermore, HIF1 enhances glycolysis by
preventing the use of pyruvate by the mitochondria
through the upregulation of PDK1, which phosphorylates
PDH1 and inhibits its ability to convert pyruvate to
acetylCoA as the fuel for the TCA cycle[138].
In addition to response to environmental oxygen
fluctuation, HIF1 can also be regulated by molecules
such as FH and SDH. Loss of function mutations of FH
and SH lead to the accumulation of the TCA cycle
intermediates furmate and succinate, resulting in
dependent prolyl
inhibition of the ketoglutarate
hydroxylase, thereby stabilizing HIF1[139].

is an oncogene that affects many
cellular functions including energy metabolism[20].
overexpression is estimated to be associated with at
least 40% of all cancers[140]. Similar to HIF1,
promotes glycolysis mainly through upregulation of
glycolytic
molecules
including
GLUT1,
HKII,
phosphofructokinase (PFK), enolase, and LDH[21]. It is
important to note that
also plays a major role in
promoting glutamine use in cancer cells through
upregulating the expression of glutamine transporters
and
and enhancing the expression of
GLS1 by repressing the expression of
and
thus releasing the suppressive effect of these
miRNAs on GLS1 expression[38,39].
The tumor suppressor
is a stress sensor
and cell cycle checkpoint regulator in mammalian cells
that plays essential roles in cell cycle regulation,
apoptosis, and genome stability[141]. The role of
in
energy metabolism was recognized by Matoba
.[22],
who found that loss of
diminishes the synthesis of
cytochrome oxidase (
), a nuclear DNAencoding
gene whose product is necessary for the assembly of
mitochondrial respiratory complex IV . Thus, this study
directly links
to OXPHOS. The loss of
shifted
the cellular ATP production from mitochondrial
respiration to glycolysis. Moreover, 53 protein represses
the expression of the GLUT1 and GLUT4 transporters.
enhances the expression of
Thus, the loss of
glucose transporters and further promotes glycolysis.
.[21] identified a
target
Interestingly, Benssad
gene known as TP53induced glycolysis and apoptosis
), which is a potent glycolysis regulator.
regulator (
Expression of
decreases the intracellular level of
fructose2,6bisphosphate, which otherwise suppresses
glycolysis by shunting glucose to the PPP[142]. In addition,
515
also affects energy metabolism by regulating AMPK,

mTOR, PTEN, and IGFbinding protein3[143].
mutations are found in approximately 30%
of all human cancers[144] and are important in promoting
cancer initiation and progression[145].
, the most
commonly mutated oncogenic
in pancreatic cancer,
has been shown to affect the shape and function of the
mitochondria during fibroblast transformation[146]. Further
studies showed that fibroblasts transformed by activated
attenuated OXPHOS by suppressing the activity
of respiratory complex I, with a corresponding decrease
in the expression level of complex I proteins[147]. Similarly,
transformed mouse fibroblasts exhibited low
mitochondrial respiration, an increased dependency on
glycolysis, a sensitivity to glycolytic inhibitors, and an
insensitivity to OXPHOS inhibitors[148]. However, a recent
study showed that
may affect the synthesis of the
mitochondrial phospholipid cardiolipin and that the
led to increased respiration[149],
absence of
suggesting that the effect of
on mitochondrial
respiration is likely complex and requires further study.
Therap eutic approaches targeting cancer cell

metabolism
Although metabolic alterations in cancer cells are
Therapeutic approach
Metabolic target
Inhibition of glycolysis HK
HK VDAC complex
LDH & lactate transport
PDK
Glucose transporter
Phosphofructokinase
Pyruvate Kinase
Interfering glutamine
Glutamine (analogs)
metabolism
Glutamine
Glutamine transport
Glutaminase
Transaminase
Targeting energy
AMPK
sensors & regulators HDAC
HIF 1
AKT
PI3K
mTOR
highly complex and the detailed underlying mechanisms

remain to be elucidated, the unique metabolic profiles in
cancer cells may serve as a biochemical basis for
developing new therapeutic strategies to effectively kill
the malignant cells with high selectivity. For cancer cells
that are highly dependent on glycolysis, inhibiting
glycolysis seems to be a logical therapeutic strategy.
Similarly, interference with glutamine metabolism may
significantly impact cancer cells that depend on
glutamine for survival and proliferation. Due to the
metabolic adaptability of cancer cells, it may be
necessary to combine agents that target different
metabolic pathways to achieve high therapeutic activity.
The following sections describe several therapeutic
strategies that target various metabolic pathways
important for cancer cells. The representative
compounds are listed in Table 1.
Inhibition of the glycolytic pathway

HKII has been shown to be elevated in cancers and
possibly upregulated by HIF1[150152]. 2Deoxyglucose
(2DG), a nonmetabolically active glucose analog that
inhibits HKII and represses tumor growth, is currently in
clinical trials for cancer treatment[153,154]. 2DG preferentially
kills cancer cell exhibiting mitochondrial defects or under
hypoxia[155157]. Combination of 2DG with cisplatin has
Agent
References
2 Deoxyglucose, 3 bromopyruvate Lonidamine

Methyl jasmonate
Oxamate, shRNAs, cyano 4 hydroxy cinnamic acid
Dichloroacetate
Phloretin
PFKFB3 3(3 pyridinyl) 1 (4 pyridinyl) 2 p, 3PO, Clotrimazole
CAP 232/TLN 232
6 Diazo 5 oxo L norleucine, azaserine, acivicin
L Asparaginase, phenylbutyrate,
L glutamyl p nitroanilide (GPNA),
Compound 968, 6 diazo 5oxo norleucine
Amino oxyacetic acid
Metformin thiazolidinediones, AICAR
Romidepsin, SAHA
Romidepsin,
NSC 644221,
RX 0047
Genistein, celecoxib, perifosine, GST anti Akt1 MTS
LY294002, wortmannin
Rapamycin, Temsirolimus (CCI 779), Everolimus (RAD 001)
[153-158, 217, 218]

[120, 160-162]
[3, 171, 173, 174]
[170, 175, 176]
[177]
[178, 179, 219]
[217]
[182-184, 191]
[181, 185, 186]
[33, 192]
[40, 193]
[33, 195, 196]
[199-202, 220]
[205, 206]
[206]
[189]
[190]
[207, 208]
[209]
[211-213]
HK, hexokinase VDAC, voltagedependent anion channel LDH, lactate dehydrogenase PDK, pyruvate dehydrogenase kinase
AMPK, AMPactivated protein kinase HDAC, histone deacetylase SAHA, suberoylanilide hydroxamic acid AICAR,
5aminoimidazole4carboxamide ribonucleotide HIF1: hypoxiainducible factor1 mTOR: mammalian target of rapamycin.
been shown to increase cytotoxicit y through oxidative

stress in human head and neck cancer cells [153].
Increased cytotoxic effects were also observed when
2DG was combined with adriamycin and paclitaxel in
mice bearing human osteosarcoma and in the MV522
nonsmall cell lung cancer xenograft model[158].
3Bromopyruvate (3BrPA), another inhibitor of HKII,
has been shown to be effective in killing lymphoma and
colon cancer cells as well as other cancer cells with
mitochondrial defects[92]. Consistent with its ability to
inhibit glycolysis, 3BrPA is particularly effective against
cancer cells under hypoxia, a condition where cells
become highly dependent on glycolysis. Interestingly,
Chen
.[159] reported that 3BrPA triggered leukemia
cell death by disrupting the association between HKII
and apoptosisinducing factor in the mitochondria.
Similarly, the plantderived methyl jasmonate or the HKII
amino terminusderived peptide TATHK can also disrupt
the
association
between
hexokinase
and
the
voltagedependent
anion
channel
(VDAC),
a
phenomenon observed more in cancer cells compared to
normal counterparts [120,160,161]. In a recent study, methyl
jasmonate was found to activate the PI3K/Akt pathway in
sarcoma cell lines, whereas its combination with
2deoxyD glucose to inhibit glycolysis resulted in a
synergistic cytotoxic effect[162].
Lonidamine, a derivative of indazole3carboxylic
acid, was shown to inhibit tumor growth through inhibition
of HKII, depletion of ATP, reduction of oxygen
consumption, and lactate production[163165]. Combination
of lonidamine with chemotherapeutic drugs such as
doxorubicin and cisplatin have been tested in clinical
trials in breast cancer, ovarian cancer, glioblastoma, and
nonsmall cell lung cancer[166169]. In addition to its
applications in cancer treatment, lonidamine was
developed by Threshold Pharmaceuticals as TH070 to
treat benign prostatic hyperplasia (BPH). Unfortunately,
clinical trials of TH070 in patients with BPH did not
show a significant therapeutic effect, and the
development of TH070 was discontinued in 2006. It
should be noted, however, that the ability of lonidamine
to inhibit glycolysis and its potent effect against cancer
cells suggest that this compound may still have potential
value in cancer treatment, especially for the highly
glycolytic cancer types.
A logical approach to target glycolysis is to inhibit
LDH, which is an NADHdependent enzyme that
converts pyruvate to lactate and has been shown to be
elevated in certain cancer cells[3,170]. Inhibition of LDH has
been demonstrated by use of oxamate, resulting in
reduced glycolytic rate, decreased glucose uptake, and
suppressed growth of HeLa cells[171]. Combination of LDH
inhibition with doxorubicin resulted in enhanced ATP
www.cjcsysu.com
depletion and overall cyto toxicity [172]. Additionally,

acid is an agent that inhibits
cyano4hyroxycinnamic
lactate transport and, thus, can affect lactate metabolism

and potentially interfere with glycolysis in cancer
cells[173,174].
Another strategy for inhibiting the glycolytic process
is targeting PDK. PDK phosphorylates PDH, resulting in
inhibition of PDH activity[170]. Dichloroacetate inhibits PDK
and indirectly increases production of acetylCoA, which
can then enter the TCA cycle, thereby switching cellular
energy metabolism from glycolysis to mitochondrial
OXPHOS. This compound has been previously used in
treating lactic acidosis and seems to be well tolerated in
young children [175]. Bonnet
. [176] showed that
dichloroacetate reduced tumor cell proliferation and
increased apoptosis by activating the expression of the
K+ (Kv1.5) channel through nuclear factor of activated T
cells and by reducing the mitochondrial membrane
potential in tumor cells . The therapeutic activity of
dichloroacetate for cancer remains to be evaluated in
clinical trials.
Additionally, as glycolysis is dependent on glucose
uptake, inhibiting glucose transporters is an alternate
method to repress active glycolysis often observed in
cancer cells. Phloretin is a glucose transporter inhibitor
reported to induce apoptosis and overcome drug
resistance in hypoxic conditions[177]. Moreover, since PFK
is an important regulatory enzyme in glycolysis, it is
considered a highimpact target for antitumor drugs[178].
PFKFB33(3pyridinyl)1(4pyridinyl)2propen1one(3PO),
a smallmolecule inhibitor, was shown to inhibit PFK
activity, reduce glucose uptake, and suppress tumor
growth in several human malignant hematopoietic and
adenocarcinoma cell lines[179].
Although many cancer cells are highly dependent on
the glycolytic pathway, certain tumor cells, including
those of the lung, mammary glands, skin, and cervix,
are active in OXPHOS[94]. Therefore, it must be noted
that the metabolic profiles of tumor cells are dependent
on the cancer type, microenvironment, differentiation,
and cancer stage. Further, inhibiting glycolysis may not
be a universal strategy to target cancer metabolism.
Inhibition of glutamine metabolism

The dependency of certain cancer cells on
exogenous glutamine for survival has been referred to as
glutamine addiction , which renders cancer cells highly
sensitive to glutamine starvation[180,181]. Early studies have
shown that glutamine analogues, such as 6diazo5oxo
Lnorleucine (LDON), azaserine, and acivicin, exhibited
potential anticancer activity, but the efforts to develop
these compounds as therapeutic drugs were hampered
due in part to potential neurotoxicity, gastrointestinal
517
toxicity, and myelosuppression[182184]. Interestingly, a

recent study showed that inhibition of glutamine metabol
ism using LDON suppressed cancer metastasis in a
mouse model of breast cancer[6].
Another approach to inhibit glutamine metabolism is
to lower the glutamine levels in blood using agents such
as Lasparaginase and phenylbutyrate. Lasparaginase,
an enzyme that hydrolyzes asparagine to aspartic acid,
has been used successfully in treating pediatric acute
lymphoblastic leukemia[185], as these particular leukemia
cells
are
unable
to
synthesize
asparagines.
Lasparaginase can also hydrolyze glutamine to glutamic
acid and ammonia, thereby depleting glutamine in the
blood [181,186]. Phenylbutyrate, also known as Buphenyl
(Ucyclyd Pharma) or Ammonaps (Swedish Ophan
International), is an FDAapproved agent for the
treatment of hyperammonemia. This compound is
metabolized in the human body to phenylacetate, which
is
then
conjugated
with
glutamine
to
form
phenylacetylglutamine for excretion by the kidneys. As
such, phenylbutyrate is able to deplete plasma glutamine
levels. Phenylacetate has also been used in patients with
various cancers and other medical conditions[187189].
Glutamine transporters such as SLC1A5 (ASCT2)
and SLC1A7 are upregulated in cancers, making them
attractive targets for the suppression of glutamine
uptake[38,39,190]. Recent studies also suggest that glutamine
levels affect activation of mTORC[191]. ILglutamylp
nitroanilide (GPNA) is a SLC1A5 inhibitor shown to

inhibit
glutamine
uptake
and
attenuate
glutaminedependant mTOR activation, leading to
induction of autophagy in cancer cells[33,192].
Cancer cells display increased activity in
glutaminase, an enzyme responsible for hydrolyzing
glutamine to glutamate and ammonia. This enzyme
seems to play an important role in energy metabolism
and survival of certain cancer cells, thus providing a
therapeutic window through its inhibition[193]. Human Bcell
lymphoma and prostate cancer cells show increased
plays
glutaminase expression, and the oncogene
a major role in promoting glutaminase expression
[39]
. Similarly, breast
through downregulation of
cancer cell line MDAMB231 showed a higher expression
of glutaminase when compared to normal mammary
epithelial cells[40]. A small molecule known as compound
968 has been shown to inhibit glutaminase and suppress
oncogenic transformation [40]. Conversion of glutamine to
as a metabolic intermediate for the TCA
ketoglutarate
cycle was demonstrated as essential for activating

that promote
various pathways involving
tumorgenesis. As the main route through which
glutamine enters the TCA cycle is transamination, the
transaminase inhibitor aminooxyacetic acid (AOA) has
been suggested as potential therapeutic agent for
cancer[194]. AOA exerts a cytotoxic effect on glutamine
dependent Mycamplified glioblastoma cells and inhibits

breast cancer cell growth in a mouse xenograft
model[33,195]. This compound has also been shown to
sensitize melanoma cells to TRAILmediated killing by
interfering with glutamine metabolism[196].
Targeting the energy sensors and regulators

AMPK, an
evolutionarily conserved enzyme that plays a pivotal role
in maintaining cellular energy homeostasis[197], is activated
by an elevated ratio of AMP/ATP under various stress
conditions, such as hypoxia, glucose deprivation, and
oxidative stress. As described earlier, activated AMPK
has an effect on various molecules that are involved in
cancerrelated cellular processes. A recent study
examined the role of AMPK in breast cancer progression
and showed that reduced expression of AMPK in breast
cancer specimens was inversely correlated with axillary
node metastasis and histological grade, suggesting an
important role of AMPK signaling in cancer progression
and metastasis[198]. These observations also imply that
activation of AMPK might have therapeutic potential in
cancer treatment. Biguanides and thiazolidinediones, two
classes of compounds used in treating diabetes, can
activate AMPK. A clinical study that involved treating
diabetic breast cancer patients with or without the AMPK
activator metformin (biguadine) showed that patients in
the metformin treatment arm exhibited complete
pathologic responses [199]. The antitumor effect of
troglitazone (thiazolidinedione) has been demonstrated in
.
various cancer cells involving activation of PPAR [200,201]
Similarly, 5aminoimidazole4carboxamide ribonucleoside

reversed the sensitivity of Aktexpressing glioblastoma
cells to glucose deprivation by activation of AMPK[202].
Another metabolic therapeutic approach involves the use
of histone deacetylase
(HDAC) inhibitors. AMPK
activation promotes the phosphorylation of mitochondrial
acetylCoA carboxylase, leading to fatty acid and
cholesterol synthesis, while acetylCoA is necessary for
histone acetylation[203]. Therefore, epigenetic regulation
can be modulated by metabolic factors with therapeutic
potential in cancer[204]. The HDAC inhibitor suberoylanilide
hydroxamic acid was found to induce oxidative stress,
autophagy, and apoptosis in imatinibresistant chronic
myelogenous leukemia[205]. Romidepsin, another HDAC
inhibitor, is in clinical phase II trials for the treatment of
refractory myeloma and has been shown to inhibit the
HIF1 pathway[206].
The PI3K/AKT/
mTOR signaling pathway plays a key role in energy
metabolism and regulates cell growth and proliferation in
a variety of tumor cells, thereby serving as a critical
target for cancer therapy. Genistein, celecoxib, and
perifosine are pharmacologic agents that target

and
have been tested for treating prostate cancer[207]. A cell
permeable
antibody that blocks the catalytic site of
AKT is effective in triggering cell death in various cancer
cell lines [208]. The PI3K inhibitors LY294002 and
wortmannin and other derivatives have been investigated
in various types of cancer [209]. The mTOR pathway can
activate the transcription factor HIF1 and enhance
angiogenesis and glycolysis while downregulating
OXPHOS, rendering tumor cells more glycolytic and
aggressive[210]. Rapamycin has been shown to have an
anticancer effect, and other mTOR inhibitors such as
temsirolimus (CCI779) and everolimus (RAD001) are
currently in clinical trials for cancer treatment [211213].
Inhibition of mTOR leads to profound change in cellular
metabolism and attenuation of protein synthesis.
The
oncogene contributes to cancer development
by encoding a transcription factor cMyc, which plays a
key role in cellular metabolism to carcinogenesis[20].
affects metabolism through its ability to regulate various
genes involved in glucose and glutamine metabolism,
including GLUT1, HKII, PFKM, enolase, LDHA, and
glutaminase. Similarly, HIF1 also plays a major role in
sensing changes in microenvironment and promotes
glycolysis through regulation of glycolytic enzymes.
Various strategies are currently being explored to target
these important regulatory molecules and their
downstream effectors for potential use in cancer
treatment[214220].
Concluding Remarks
An increase in aerobic glycolysis, first reported by
Otto Warburg more than 80 years ago, represents the
most prominent metabolic alteration observed in cancer
cells. Other important metabolic changes, such as
glutamine addiction and active OXPHOS in certain tumor
cells, were subsequently discovered. The differences
between cancer cells and normal cells in their energy

metabolism provide a biochemical basis for developing
new therapeutic strategies to preferentially kill cancer
cells
with
selectivity
using
metabolismtargeted
compounds. Inhibiting
glycolysis
and
interfering
glutamine metabolism are two possible metabolic
intervention
approaches.
Additionally,
emerging
metabolic profiling of cancer stem cells will also provide
new
therapeutic
opportunities.
Mitochondrial
dysfunctions, activation of oncogenes, loss of tumor
suppressors, and tumor tissue microenvironment
conditions are known to profoundly affect the metabolism
of cancer cells, rendering heterogeneous metabolic
profiles among different cancer types. As such, it is
important to determine the specific metabolic alterations
in each particular cancer type so that effective cancer
typespecific metabolic intervention strategies can be
developed. Furthermore, a combination of conventional
chemotherapeutic agents and metabolic modulators may
enhance therapeutic activity and should be further
evaluated. It should be cautioned, however, that as
energy metabolism and its regulatory machinery are
evolutionarily conserved and shared by various normal
cells, metabolic inhibitors are likely to affect normal cells
to various degrees. Despite a number of pharmacologic
agents that show promising results in preclinical studies,
whether the metabolic alterations in cancer cells can be
targeted efficiently and safely in the clinic has yet to be
determined. Thus, it is vitally important to identify the
metabolic steps that are altered and critical in cancer
cells but dispensable in normal cells as the valid
therapeutic targets, which will enable the development of
effective agents to improve cancer treatment outcomes.
A comprehensive understanding of the metabolic
differences between cancer and normal cells through
detail investigation will pave the way to achieve this goal.
Received: 20110627 revised: 20110714

accepted: 20110714.
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Metabolic Alterations in Cancer Cells

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Chinese Journal of Cancer

Cancer cells have long been known to exhibit

Peng Huang, Department of Molecular

Anti Cancer A ssociation

Naima Hammoudi et al.

mTOR, a downstream target of AKT, seems to function

Metabolic Alterations in Cancers

Cancer metabolism and therapeutics

further metabolized through the Kreb s cycle and the

Glutamine in cancer metabolism

Chin J Cancer; 2011; Vol. 30 Issue 8

Naima Hammoudi et al.

Cancer metabolism and therapeutics

glutamate, correlates with tumor growth, and that

source of malate, oxaloacetate, and NADPH for fatty

510 Chin J Cancer; 2011; Vol. 30 Issue 8

regulated by the oncogene c

Chinese Journal of Cancer

Naima Hammoudi et al.

play a role in cancer metastasis. Seyfried

Alterations of metabolic enzymes in cancers

Cancer metabolism and therapeutics

been reported in hereditary leiomyomatosis, renal cell

hydroxylases and HIF1, which catalyze a host of

Metabolic alterations in cancer stem cells

Chin J Cancer; 2011; Vol. 30 Issue 8

Naima Hammoudi et al.

of cancer stem cells in an undifferentiated state[63,64].

M etabolic Alterations and Drug Resis

512 Chin J Cancer; 2011; Vol. 30 Issue 8

Cancer metabolism and therapeutics

used respirationdeficient 0 cells to investigate the role

.[77] reported that although staurosporine treatment

Chinese Journal of Cancer

Naima Hammoudi et al.

Cancer metabolism and therapeutics

resistance associated with mitochondrial respiration

After his initial observation of increased glycolysis in

Mitochondria mutations in cancers

source of ROS generation makes mtDNA highly prone to

Chin J Cancer; 2011; Vol. 30 Issue 8

Naima Hammoudi et al.

Cancer metabolism and therapeutics

The human mitochondrial genome is a 16.5

Additionally, mtDNA mutations have been detected in

Role of oncogenes and tumor suppressor genes

514 Chin J Cancer; 2011; Vol. 30 Issue 8

and activation of certain oncogenes.

Chinese Journal of Cancer

Naima Hammoudi et al.

glucose6phosphate for use in glycolysis and other

AMPK activation [128]. AMPK activation in turn induces

Cancer metabolism and therapeutics

glucose metabolism from OXPHOS to glycolysis when

hydroxylase, thereby stabilizing HIF1[139].

Chin J Cancer; 2011; Vol. 30 Issue 8

Naima Hammoudi et al.

Cancer metabolism and therapeutics

also affects energy metabolism by regulating AMPK,