CELL SCIENCE AT A GLANCE ARTICLE SERIES: CELL BIOLOGY AND DISEASE
Cancer metabolism at a glance
Alexei Vazquez
1
, Jurre J. Kamphorst
1,2
, Elke K. Markert
1,2
, Zachary T. Schug
1,
*, Saverio Tardito
1
and Eyal Gottlieb
1,‡
ABSTRACT
A defining hallmark of cancer is uncontrolled cell proliferation. This
is initiated once cells have accumulated alterations in signaling
pathways that control metabolism and proliferation, wherein the
metabolic alterations provide the energetic and anabolic demands of
enhanced cell proliferation. How these metabolic requirements are
satisfied depends, in part, on the tumor microenvironment, which
determines the availability of nutrients and oxygen. In this Cell
Science at a Glance paper and the accompanying poster, we
summarize our current understanding of cancer metabolism,
emphasizing pathways of nutrient utilization and metabolism that
either appear or have been proven essential for cancer cells. We also
review how this knowledge has contributed to the development of
anticancer therapies that target cancer metabolism.
KEY WORDS: Cancer, Metabolism, Targeted therapy
Introduction
Cancer cells typically proliferate from one aberrant cell to more than
10
9
cells (the average number of cells in a tumor of ∼1cm in
diameter). To achieve and sustain that proliferative capacity, cancer
cells must activate or enhance metabolic pathways (Lunt and
1
Cancer Metabolism Research Unit,Cancer ResearchUKBeatson Institute, Garscube
Estate, Switchback Road, Glasgow G61 1BD, UK.
2
Institute of Cancer Sciences,
University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK.
*Present address: Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
‡
Author for correspondence (e.gottlieb@beatson.gla.ac.uk)
E.G., 0000-0002-9770-0956
This is an Open Access article distributed under the terms of the Creative Commons Attribution
License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution and reproduction in any medium provided that the original work is properly attributed.
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© 2016. Published by The Company of Biologists Ltd
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Journal of Cell Science (2016) 129, 3367-3373 doi:10.1242/jcs.181016
Journal of Cell Science
Vander Heiden, 2011). These pathways use available nutrients
to generate the metabolic precursors for cell anabolism, to satisfy
the energy demand for cell maintenance and biosynthesis and to
maintain the reduction–oxidation (redox) balance in the cell. The
dry mass of mammalian cells is, for the most part, composed of
proteins, lipids and nucleotides that are synthesized from metabolic
precursors. Amino acids are the building blocks of proteins, acetyl-
CoA is a precursor of lipids, and purines and pyrimidines form the
backbone of nucleotides; these metabolic precursors are synthesized
de novo from different nutrients.
Here, we provide a concise graphical depiction of major
metabolic pathways that are employed by cancer cells to sustain
survival and proliferation. We also briefly describe these metabolic
pathways from a nutrient-based perspective, and the outline follows
the hierarchy of nutrient utilization by cancer cells. We start with
glucose, the most abundant nutrient in the blood and, not
surprisingly, the major contributor to the evolution of the
metabolism of mammalian cells. We continue with glutamine, the
second most consumed nutrient after glucose, followed by serine
and other amino acids. We briefly discuss the role of fatty acid
synthesis and highlight some recent discoveries about acetate as a
potential source for the synthesis of lipids. Very con cisely, we
also go over the role of oxygen as both an electron acceptor
supporting energy generation and the source of reactive oxygen
species (ROS). Additionally, we review the role of scavenging
during nutrient deprivation. Finally, in a departure from our
nutrient-based perspective, we briefly discuss the concept of
oncometabolites that link core metabolic pathways with cancer
signaling and epigenetics.
Glucose
Normally, mo st of the glucose consumed by cells is catabolized
through glycolysis to pyruvate, which is transported to the
mitochondria. In the mitochondria of aerobic cells, pyruvate fuels
the tricarboxylic acid (TCA) cycle and the electron transport chain
(ETC), where oxidative phosphorylation takes place. Gluc ose
catabolism coupled to oxidative phosphoryl ation has a high
energy yield in the form of ATP. Cancer cells, paradoxically,
convert much of the pyruvate into lactate, which is then excreted to
the extracellular medium (see poster). The catabolism of glucose
into lactate has an extremely low energy yield and, consequently,
cancer cells require a high glucose consumption rate to satisfy their
energy and anabolic demands. A high rate of glucose catabolism
into lactate (glucose fermentation) is the most ubiquitous metabolic
phenotype seen across cancer cells and was first reported by
Warburg (1956). The transport of lactate out of cells is facilitated by
monocarboxylate transporters (MCTs) and, given that they are
required to sustain the high rates of glycolysis in cancer cells, MCTs
are candidate targets for cancer therapy (Doherty and Cleveland,
2013) (see poster table).
In cells, glucose is also a major carbon source for biosynthesis.
The pyruvate derived from glucose contributes to the synthesis of
acetyl-CoA, a precursor of fatty acid, lipid and cholesterol synthesis.
Pyruvate also participates in the synthesis of the non-essential
amino acids aspartate and asparagine, via the activities of pyruvate
carboxylase and glutamate and oxaloacetate transaminases (GOT1
and GOT2). Other intermediate metabolites of glycolysis are also
biosynthetic precursors. Glucose 6-phosphate (G6P) is the
branching point from glycolysis to the oxidative branch of the
pentose phosphate pathway (PPP), which generates the ribose group
required for the synthesis of nucleotides. The PPP is also a major
pathway for NADPH generation. Finally, 3-phosphoglycerate
(3PG) is the branching point for the synthesis of the non-essential
amino acid serine (discussed below).
In summary, cancer cells use the catabolism of glucose through
glycolysis as a major energy-generating pathway. In addition, several
biosynthetic molecules and NADPH are generated from glucose.
Glutamine
Glutamine, alongside alanine, redistributes nitrogen and carbons
between source- and sink-organs for these elements. In accordance
with its pleiotropic functions, glutamine is the most abundant
circulating amino acid in humans. Under in vitro cell culture
conditions, glutamine is the second most consumed nutrient after
glucose, and its consumption exceeds its demand for protein
synthesis (Jain et al., 2012). However, a high proportion of the
consumed glutamine is generally de-amidated and released into the
medium as glutamate (Bannai and Ishii, 1988; Jain et al., 2012;
Timmerman et al., 2013). The export of glutamate is often coupled
to cystine import through the xCT antiporter (Bannai and Ishii,
1988; Timmerman et al., 2013). Glutamate is produced from
glutamine by several amidotransferase-catalyzed reactions, while
the amidic nitrogen of glutamine is transferred to metabolic
intermediates, such as asparagine, nucleotides and glucosamine
phosphate. Additionally, glutaminases (GLS and GLS2) hydrolyze
glutamine to glutamate and inorganic ammonia. Inhibition of GLS
has shown anti-tumor effects in several cancer models, and one such
inhibitor is currently under clinical investigations (Gross et al.,
2014; Jacque et al., 2015; Shroff et al., 2015). However, the efficacy
of GLS-targeted therapies appears to be affected by cell culture
conditions (Davidson et al., 2016). In addition, xCT, which exports
glutamate from the cell, had a pro-tumorigenic effect in glioma
patients and triple negative breast cancer models (Robert et al.,
2015; Timmerman et al., 2013).
Glutamine-derived glutamate can also be produced in excess of
its demand for protein synthesis. The excess glutamate is either
exported to the extracellular medium (Jain et al., 2012) or converted
into α-ketoglutarate (αKG) by glutamate dehydrogenase (GDH) or
transaminases. αKG can be metabolized in the TCA cycle, either
oxidatively or reductively, and, hence, it contributes to anaplerosis,
the replenishing of TCA cycle metabolites. The synthesis of citrate
from αKG through reductive carboxylation has been reported to be
essential for growth of cancer cells with mitochondrial defects
(Mullen et al., 2012), suggesting that these cancers cou ld be
distinctively sensitive to the inhibition of glutamine metabolism.
Glutamine synthetase, which catalyzes the ATP-dependent
condensation of glutamate and ammonia, is the only enzyme able
to synthesize glutamine. In hepatocellular carcinoma (HCC),
activating mu tations in β-catenin increase the expression of the
glutamate transporter (EAAT2, also known as SLC1A2), as well as
of glutamine synthetase (Cadoret et al., 2002; Dal Bello et al.,
2010). Glutamine synthetase inhibition and glutamine depletion
hamper the growth of HCC xenografts (Chiu et al., 2014),
suggesting that high glutamine levels could be instrumental for
the metabolism of liver tumors, independently of its anaplerotic
function. In line with tissue-specific differences in glutamine
utilization (Yuneva et al., 2012), the availability of circulating
glutamine is limited. Accordingly, glutamine synthetase activity in
either stem-like cancer cells or in neighboring astrocytes is required
for glutamine supplementation to glutamine-synthetase-negative
glioblastoma cells (Tardito et al., 2015). The anaplerotic
contribution of glutamine has been shown to sustain the anabolic
metabolism of cultured cancer cells derived from various tissues. On
these bases, GLS has been identified as a potential therapeutic
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target for ‘glutamine-addicted’ tumors. However, the validity of
this phenotype awaits confirmation in pre-clinical models where
the glutaminase-dependent anabolic contribution appears to be
downsized (Davidson et al., 2016; Tardito et al., 2015).
Thus, the pro-growth effect of glutamine cannot be solely
explained by carbon metabolism, and the central role of this
pleiotropic amino acid in nitrogen metabolism, as well its
contribution to signaling events, must be considered to fully
understand the multifaceted relationship between glutamine and
cancer.
Serine and one-carbon metabolism
The non-essential amino acid serine can be either imported from the
medium or synthesized from the glycolytic intermediate 3PG. The
first step of serine synthesis is catalyzed by 3PG dehydrogenase
(PHGDH), an enzyme that is often genetically amplified in breast
cancers (Possemato et al., 2011) and melanoma (Locasale et al.,
2011). This has motivated the investigation of PHGDH as a target
for cancer therapy. Serine is the third most consumed metabolite by
cancer cells after glucose and glutamine (Dolfi et al., 2013;
Jain et al., 2012). A significant amount of serine is
converted into glycine (Maddocks et al., 2013; Tedeschi et al.,
2015a) through the activity of cytosolic or mitochondrial serine
hydromethyltransferases (SHMT1 and SHMT2). In this reaction,
serine releases a one-carbon unit to the one-carbon pool. In
principle, glycine could also contribute to the one-carbon pool
through the glycine cleavage system. However, the available data
indicates that serine is the major donor of one-carbon units in cancer
cells and that glycine cannot substitute for serine (Labuschagne
et al., 2014).
The one-carbon unit donated by serine is utilized in the
biosynthesis of thymidine monophosphate (dTMP) and purines,
and the available evidence suggests that specific one-carbon pools
are located in different cellular compartments (see poster). For
instance, the one-carbon stock for dTMP synthesis is generated in
the cytosol in a cyclical pathway involving SHMT1, thymidylate
synthase (TYMS) and the co-enzyme folate in the form of
dihydrofolate (DHF) and tetrahydrofolate (THF) (see poster, 1C
cycle cytosol II; Oppenheim et al., 2001). Indeed, TYMS and DHF
reductase (DHFR) are the targets of some of the earliest anti-cancer
drugs, such as 5-fluoracil and methotrexate (Wilson et al., 2014)
(see poster table).
In contrast, the one-carbons required for purine synthesis are
generated in the mitochondria (see poster, 1C cycle mitochondrion,
Lewis et al., 2014). The mitochondrial one-carbon units are
transferred to and from THF via SHMT2, 5,10-methenyl-THF
dehydrogenase 2 (MTHFD2) and 10-formyl-THF synthase
(MTHFD1L), releasing the one-carbon unit as formate. Formate
is then transported to the cytosol where it is ligated to THF by
cytosolic 10-formyl-THF synthase (MTHFD1) to generate the
cytosolic 10-formyl-THF that transfers the one-carbon units to
purines (see poster, 1C cycle cytosol I). MTHFD2 is expressed
mostly in embryonic and cancer tissues, whereas in the
mitochondria of normal adult tissues, MTHFD2 activity is carried
out by the product of a different gene, MTHFD2L (Bolusani et al.,
2011). This observation points to MTHFD2 as a potential target
for cancer therapy (Nilsson et al., 2014; Tedeschi et al.,
2015b). SHMT2 has been shown to drive cancer cell growth
in different contexts (Kim et al., 2015; Ye et al., 2014). Furthermore,
high SHMT2 in cancer cells creates a dependency on glycine
clearance that could be exploited for anticancer therapy (Kim et al.,
2015).
Taken together, the discovery of the genes coding for
mitochondrial one-carbon metabolism enzymes has led to a
significant advance in our understanding of mitochondrial one-
carbon metabolism in normal and cancer cells. It remains to be
elucidated whether new drugs specifically targeting mitochondrial
one-carbon metabolism have anti cancer activity.
Methionine and m ethylation
In addition to nucleotide metabolism, the one-carbon pool is required
for methylation processes, which are crucial for epigenetic regulation
of gene expression. The essential amino acid methionine can be
either imported into cells or recycled through the methylation cycle.
In the canonical methylation cycle, methionine is converted into
S-adenosyl-methionine (SAM) through the activity of methionine
adenosyltransferase transferase (MAT). Here, SAM provides a
methyl group and is converted into S-adenosylhomocysteine
(SAH). SAH is then hydrolyzed to adenosine and homocysteine.
Finally, methionine synthase transfers a one-carbon unit from
5-methyl-THF to homocysteine, thereby regenerating methionine.
In vitro data from different cell lines indicate that this methylation
cycle is truncated in cancer cells and that methionine synthase
activity is negligible compared with the rate of methionine
consumption (Mentch et al., 2015; Shlomi et al., 2014; Tedeschi
et al., 2015a). Homocysteine is not recycled back to methionine, but
is instead secreted from cells (Shlomi et al., 2014). However, this
in vitro evidence does not exclude the possibility that, in vivo,
methionine synthase provides a higher contribution to the
methylation cycle, particularly during conditions of nutrient
starvation.
Arginine, ornithine and the urea cycle
Both the non-essential amino acid arginine and the non-proteogenic
amino acid ornithine contribute to cancer cells beyond protein
synthesis. Arginine and ornithine can be imported into cells, and
arginine can be converted into ornithine through the activity of
arginase (ARG1 and ARG2). Ornithine, a precursor of polyamine
synthesis, is essential for cell proliferation (Pegg, 2009). The first
step of polyamine synthesis is catalyzed by ornithine decarboxylase
(ODC1). 2-Difluoromethylornithine is an irreversible inhibitor of
ODC1; however, it failed as a single agent in multiple clinical trials
(Casero and Marton, 2007). Arginine and ornithine are both
intermediate metabolites of the urea cycle, although it is not clear
whether this cycle plays a significant role in cancer cell metabolism.
In cancer cells with fumarate hydratase deficiency, the urea cycle
step catalyzed by argininosuccinate lyase (ASL) manifests a high
rate of synthesis of argininosuccinate from fumarate and arginine,
allowing these cells to utilize, and decrease the levels of, the
fumarate generated by the truncated TCA cycle, at the expense of an
increased demand for arginine (Adam et al., 2013; Zheng et al.,
2013).
In many types of cancers, the expression of argininosuccinate
synthase (ASS1) is silenced epigenetically, rendering the cells
dependent on an exogenous supply of arginine (Qiu et al., 2015).
ASS1 converts aspartate and citrulline into argininosucci nate,
and the loss of ASS1 supports proliferation by increasing the
availability of aspartate for nucleotide biosynthesis (Rabinovich
et al., 2015).
The sources of acetyl-CoA and fatty acid synthesis
Acetyl-CoA is the precursor for the synthesis of fatty acids and
cholesterol. Both glucose and glutamine can con tribute to the
generation of acetyl-CoA. Acetate has recently been shown to be
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yet another source of acetyl-CoA for many different cancer types,
including breast, prostate, liver, primary glioblastomas and brain
metastases. Some of these cancerous tissues incorporate acetate
into fatty acids to support biomass production, whereas others
have been shown to use acetate to fuel the TCA cycle (Comerford
et al., 2014; Kamphorst et al., 2014; Mashimo et al., 2014; Schug
et al., 2015). Mechanistically, acetate is ligated to CoA by the
acyl-CoA synthetase short-chain family member 2 (ACSS2), an
enzyme that is upregulated during conditions of metabolic stress
such as low lipid availability and hypoxia. As such, acetate might
become a crucial nutritional source in poorly vascularized regions
of tumors.
The acetyl-CoA generated from glucose, glutamine or acetate (or
potentially other nutritional sources) supplies the cholesterol and
fatty acids synthesis demand of cancer cell growth. Cholesterol
synthesis from acetyl-CoA proceeds through the mevalonate
pathway. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA
reductase (HMGCR), the limiting step of the mevalonate pathway,
and are used to lower cholesterol levels in patients with
cardiovascular diseases. The epidemiological observation that
long-term treatment with statins is associated with a reduced
incidence of cancer stimulated research on the use of statins for
cancer prevention (Baandrup et al., 2015; Boudreau et al., 2010).
However to date, clinical trials designed to specifically test cancer
prevention by statin treatment have not been conclusive (Bertagnolli
et al., 2010; Cardwell et al., 2015).
The tumor-promoting effects of enhanced fatty acid synthesis
were first appreciated in the 1990s when fatty acid synthase
(FASN) expression was identified as prognostic marker of
aggressive breast cancers (Kuhajda et al., 1994). Since then,
many FASN inhibitors have been developed, but their potential on-
target toxicity remains a concern in clinical trials (Pandey et al.,
2012), warranting investigation into other anti-lipid metabolism
drugs. Another promising target in the field is stearoyl-CoA
desaturase (SCD) (Mason et al., 2012), for which multiple studies
have identified a crucial role in tumor growth (Fritz et al., 2010;
Scaglia and Igal, 2008). Biochemically, given that SCD inhibition
is often rescued by oleic acid supplementation (Griffit hs et al.,
2013), SCD maintains a balance between the saturated and
unsaturated fatty acid content within the phospholipid pools.
Loss of this balance often leads to ER stress and apoptosis
activation (Potze et al., 2016; Young et al., 2013). Besides lipid
synthesis, lipid breakdown also appears to be a common feature of
cancer development. The tendency of ovarian cancers to
metastasize to the omentum has been shown to be driven by
crosstalk between adipocytes and ovarian cancer cells (Nieman
et al., 2011). Cytokine signaling by the ovarian cancer cells
induces adipocytes to mobilize lipid stores. The released fatty acids
are scavenged by the invading ovarian cells and, through the
expression of fatty acid binding protein 4 (FABP4), fatty acids are
channeled into the fatty acid oxidation machinery for energy
production. The uptake of fatty acids not only by the tumor cells
but also the stromal compartment can affect tumorigenesis. Many
stromal and fat cells of human breast tumors strongly downregulate
the fatty acid scavenging protein CD36 (DeFilippis et al., 2012).
Loss of CD36 in the stromal compar tment of invasive breast
cancers induces an extracellular matrix deposition and increase in
mammographic density, which is associated with poorer prognosis.
Conversely, lipoprotein lipase (LPL) and CD36 are frequently
highly expressed in breast cancer tissue, and their overexpression in
breast cancer cell lines activates a lipolytic pathway that enhances
growth in culture (Kuemmerle et al., 2011). In more aggressive
tumors, monacylglycerol lipase (MGLL)-dependent hydrolysis of
monoacylglycerols generates fatty acids used to produce signaling
lipids, such as lysophosphatidic acid and prostaglandins, that
promote migration, cancer cell survival and tumor growth (Nomura
et al., 2010). Furthermore, the specific activation of adipose
triglyceride lipase (PNPLA2; also known as ATGL) in the white
adipose tissue and skeletal muscle of cancer patients has been
linked to cachexia, suggesting that inhibition of lipases might help
alleviate the devastating problems associated with it (Das et al.,
2011).
Taken together, the targeting of lipid metabolism pathways holds
great promise and as new targets emerge, it will be interesting to see
how they synergise with current therapies.
Metabolic scavenging during nut rient starvation
Tumor areas can experience episodes of limited nutrient supply
due to poor perfusion to the degree that nutrient availability
is insufficient for maintaining proliferation or even survival.
Additionally, some tumors are chronically poorly perfused due to
low vascularization and high interstitial pressure; a good example of
this is pancreatic ductal adenocarcinoma (PDAC) (Koong et al.,
2000; Neesse et al., 2011). A well-described alternative mode of
nutrient acquisition during these periods of starvation is autophagy
or ‘self-cannibalism’ (Rabinowitz and White, 2010). An important
function of autophagy in normal cells is the removal of damaged
and dysfunctional organelles. It is a catabolic pathway used by cells
to degrade cytoplasmic content and organelles, and recycle their
components. The process utilizes autophagosomes that eventually
fuse with lysosomes for content degradation and the subsequent
release of the breakdown products. During nutrient starvation, the
breakdown products generated by autophagy (amino acids, fatty
acids, sugars, and nucleosides) help sustain energy production and
synthesis of essential cellular building blocks. In tumor cells,
autophagy has been found to be particularly important for
maintaining survival during nutrient stress (Guo et al., 2011;
Yang et al., 2011).
Although it can support cell survival during episodes of
starvation, autophagy is inherently incapable of facilitating tumor
growth, as it only recycles or consumes the intracellular biomass. To
support proliferation, exogenous substrates are required. Recently, it
was found that cancer cells, particularly those with a Ras mutation,
can internalize extracellular proteins through macropinocytosis
(Commisso et al., 2013). This is an endocytic process by which
extracellular fluid and its components are engulfed by the plasma
membrane, leading to the budding of macropinosomes in the
cytoplasm (see poster). Like autophagosomes, macropinosomes
also fuse with lysosomes and the degraded content is released to
support metabolism. In the study by Commisso et al., cell
consumption of albumin was found to reduce the dependence on
free glutamine (Commisso et al., 2013), and a later study confirmed
that macropinocytosis occurs in human tumors (Kamphorst et al.,
2015). Additionally, this process enables pancreatic cancer cells to
proliferate in medium lacking essential free amino acids (Kamphorst
et al., 2015). Although the exact signaling events downstream of
Ras that are responsible for induction of macropinocytosis remain
elusive, recently, remarkable connections were found to the nutrient
sensor mammalian target of rapamycin complex 1 (mTORC1) and
its regulation of lysosomal processing. One study showed that,
whereas under nutrient-replete conditions mTORC1 inhibition
suppressed growth, under limited amino acid availability mTORC1
inhibition actually enhances lysosomal degradation of endocytosed
proteins and hence promotes proliferation (Palm et al., 2015).
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Another study found that, regardless of mTORC1 activity, PDAC
cells have heightened lysosome biogenesis compared to their non-
tumor counterparts (Perera et al., 2015).
In summary, some cancer cells survive and even grow during
primary nutrient starvation by maintaining metabolic activity through
catabolizing both intracellular and extracellular macromolecules.
This metabolic ‘scavenging’ appears important for the growth of a
subset of tumors, such as PDAC. Conceivably, it can also form a
general mechanism of resistance to antiangiogenic therapies or other
nutrient deprivation-based strategies. As all macromolecule
catabolism pathways converge at the lysosome, inhibiting the
functioning of this organelle could provide a therapeutic
opportunity, either as a mono- or combination-therapy. Recently,
encouraging results were obtained in a phase I and II trial, in which
hydroxychloroquine (which prevents acidification of lysosomes) in
combination with gemcitabine led to a significant increase in mean
overall survival in PDAC (Boone et al., 2015).
Oxygen and reactive oxygen species
From the early observations by Otto Warburg it is known that
although cancer cells exhibit high glycolysis rates, they still retain
some mitochondrial oxidative phosphorylation activity ( Koppenol
et al., 2011). Today it is well established that cancer cells satisfy part
of their energy demand from the oxidation of glucose, glutamine
and other nutrients coupled to the electron transport chain (ETC)
(Fan et al., 2013; Hensley et al., 2016), using oxygen as the final
electron acceptor (see ETC pathway on the poster). The ETC
complex I inhibitor metformin is currently under investigation for
cancer treatment (Pollak, 2012).
Tumor cells also periodically experience hypoxic conditions (i.e.
low oxygen availability). Hypoxia results in increased glycolysis
and, correspondingly, decreased oxidative phosphorylation that is
caused either directly, due to the limitation of oxygen, or indirectly,
by the activation of the hypoxia inducible transcription factor 1 α
(HIF1A) (Kim et al., 2006; Papandreou et al., 2006). Moreover,
various oxygen-de pendent anabolic reactions might be affected by
the lack of oxygen, including the lipogenic enzyme SCD, which
introduces a double bond into the 18-carbon fatty acid stearic acid,
leading to the production of the mono-unsaturated fatty acid oleic
acid, one of the most abundant fatty acids in cells (Kamphorst et al.,
2013; Young et al., 2013). This desaturation reaction requires
molecular oxygen, and so is significantly decreased in hypoxia.
Consequently, cells become more dependent on scavenging oleic
acid from exogenous sources to maintain a proper desaturation
index (Kamphorst et al., 2013).
Mitochondrial oxygen metabolism is linked to the generation of
reactive oxygen species (ROS) (Sabharwal and Schumacker, 2014),
which, at high levels, can damage nucleotides, proteins and lipids, so
impairing cell viability. To counteract this, mammalian cells
have different pathways for ROS detoxification. In cancer cells,
glutathione (GSH) oxidation–reduction coupled to NADPH
reduction–oxidation is a major pathway for ROS detoxification (see
ROS detoxification on the poster). GSH is synthesized from the amino
acids cysteine, glutamate and glycine (see poster). GSH oxidation by
GSH peroxidase is coupled to the turnover of hydrogen peroxide
(H
2
O
2
), a major ROS byproduct of mitochondrial oxidative
phosphorylation. Oxidized glutathione (GSSG) is then reduced
back to GSH by GSH reductase coupled to NADPH oxidation.
ROS turnover through this pathway requires a supply of NADPH.
As discussed above, NADPH can be generated from glucose
from the pentose phosphate pathway or from serine via one-carbon
metabolism.
Oncometab olites
Beyond elucidating some of the catabolic, energetic and anabolic
requirements for cancer growth and survival, studies over the
past dec ade have introduced a new link between metabolic
abnormalities and cancer progression. Generally termed
‘metabolic signaling’ (Gottlieb and Tomlinson, 2005), it was
initiated by the identification of an intracellular signal transduction
cascade that is mediated by TCA cycle met abolites (Isaacs et a l.,
2005; Selak et al., 2005). In tumors that have lost the mitochondrial
tumor suppressor enzymes succinate dehydrogenase or fumarate
hy dratase, the respective accumul ation o f succinate or fum arate has
been shown to inhibit the enzymatic activity of αKG-dependent
dioxygenases, which hydroxylate HIF1A and target it for
degradation. Hence, in tumors that have lost succinate
dehydrogenase or fumarate hydratase, HIF1A is activated under
normoxic conditions, resulting in pseudohypoxia (Frezza et al.,
20 11). More rec ently, it has been shown that succinate and fumarate
are also potent modifiers of the epigenome through their role
in inhibiting other family members of the αKG-dependent
dioxygenases, namely histone or DNA demethylases (Nowicki
and Gottlieb, 2015). With the discovery of isocitrate
dehydrogenase (IDH1 and IDH2) mutations in cancer and the
associated accumulation of an unique de novo product, 2-
hydroxyglutarate (2HG), the phrase ‘oncometabolite s’ was
coined (Dang et al., 2009). 2HG has since been shown t o be a
potent epigenome regulator and this is currently considered to be its
major pro-oncogenic role (Nowicki and Gottlieb, 2015).
In summary, the discovery of IDH1 or IDH2 mutations in
human cancers has ope ned a window of opportunity for targeted
therapies against cancers harboring these mutant enzymes. The
hypothesis is that if 2HG is an oncometabolite, the inhibition of
its production should inhibit tumor growth. Ongoing clinical
trials are testing the anticancer activity of specific inhibitors of
IDH1 and IDH2 mutant enzymes and a positive outcome would
support the concept of oncometabolites, thereby providing a
productive new example of targeted therapy against canc er
metabolism.
Conclusions
Cancer metabolism has been the target of cancer therapy since the
early days of chemotherapy, with antifolates, for example, among
the first targeted treatments. Our understanding of cancer
metabolism has advanced significantly in recent years and is
being used for the development of novel targeted therapies (Olivares
et al., 2015). There are, however, several outstanding questions in
the field of cancer metabolism that are and will be the subject of
further research (see Box 1).
Box 1. Burning questions in ca ncer metabolism.
•
What is the functional relevance and selective advantage of
mitochondrial one-carbon metabolism?
•
What is the role of acetate in the interaction between metabolism and
epigenetics in cancer?
•
Under which genetic and environmental conditions does the
requirement of tumors for glutamine-derived carbon outweigh their
demand for glutamine-derived nitrogen?
•
How is macropinocytosis regulated and how important is it in
supporting growth in vivo?
•
What are the downstream factors mediating the tumorigenic activity of
oncometabolites?
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