Download Molecular Pathways: Tumor Cells Co-opt the Brain

Published OnlineFirst September 5, 2012; DOI: 10.1158/1078-0432.CCR-11-3281
Clinical
Cancer
Research
Molecular Pathways
Molecular Pathways: Tumor Cells Co-opt the Brain-Specific
Metabolism Gene CPT1C to Promote Survival
Patrick T. Reilly1 and Tak W. Mak1,2
Abstract
The metabolic adaptations of cancer cells are receiving renewed attention as potential targets for
therapeutic exploitation. Recent work has highlighted the importance of fatty acid catabolism through
b-oxidation to cellular energy homeostasis. In this article, we describe recent preclinical studies suggesting
that a gene usually expressed only in the brain, carnitine palmitoyltransferase (CPT)1C, promotes cancer cell
survival and tumor growth. CTP1C confers rapamycin resistance on breast cancer cells, indicating that this
gene may act in a pathway parallel to mTOR-enhanced glycolysis. Because of CPT1C’s normally brainrestricted expression and the inability of most drugs to pass the blood–brain barrier, CPT1C may be an ideal
candidate for specific small-molecule inhibition. We further speculate that concurrent targeting of CPT1C
activity and glycolysis in tumor cells could be a highly effective anticancer approach. Clin Cancer Res; 18(21);
1–6. 2012 AACR.
Background
Cancer cell metabolism
Tumor cells exhibit unique metabolic adaptations that
are increasingly viewed as potential targets for novel and
specific cancer therapies. A well-known example of such an
adaptation is the long-established Warburg effect in which
tumor cells exhibit defective oxidative phosphorylation
(OXPHOS; refs. 1, 2). His observation of this phenomenon
led Warburg to propose that mitochondrial dysfunction is
the primary cause of cancer. Subsequent studies have shown
that tumor cells exhibit several additional metabolic differences from normal cells, including an increased rate of
glucose uptake that feeds a high rate of glycolysis, a more
oxidative intracellular environment, and an ability to tolerate hypoxic conditions (3–5). Indeed, these properties are
collectively now considered an "emerging hallmark" of
cancer, despite their recognition decades ago (6). This
revisited recognition is based on the potential to use the
metabolic aberrations as targets for therapeutic exploitation, which, with the advent of specific small-molecule
inhibitors (7), is now practical.
Until recently, the cancer research community held a
conventional belief that increased glycolysis in a tumor cell
compensated for the cell’s loss of ATP production due to
Authors' Affiliations: 1Laboratory of Inflammation Biology, Division of
Cellular and Molecular Research, National Cancer Centre, Singapore,
Singapore; and 2The Campbell Family Institute for Breast Cancer Research,
University Health Network, Toronto, Ontario, Canada
Corresponding Author: Tak W. Mak, The Campbell Family Institute for
Breast Cancer Research, University Health Network, Toronto, Ontario,
Canada M5G 2C1. Phone: 416-946-2234; Fax: 416-204-5300; E-mail:
[email protected]
doi: 10.1158/1078-0432.CCR-11-3281
2012 American Association for Cancer Research.
defective OXPHOS. Although almost certainly part of the
explanation, this scenario is complicated by the fact that
many of the metabolites of glycolysis are diverted from
glycolytic ATP production by the cancer cell–specific
enzyme pyruvate kinase M2 (PKM2; ref. 8). Rather than
generating ATP, these metabolites are processed through the
pentose phosphate pathway (PPP) to produce additional
metabolites, for example, ribose 5-phosphate and, perhaps
more importantly, reduced NADPH, which then regenerates the reduced form of the antioxidant tripeptide glutathione (9). This antioxidant aspect of cancer metabolism is
believed to be crucial for counteracting the reactive oxygen
species (ROS) arising due to oncogene activation and the
heightened proliferation of these cells (10). The generation
of these antioxidants through the PPP, however, comes at
the cost of ATP production. Because the demand for ATP in
cancer cells is enhanced, it is likely that additional dramatic
metabolic adaptations occur in cancer cells to provide the
energy necessary for survival and proliferation (11).
Recent work has highlighted the importance of fatty acid
catabolism through b-oxidation to cellular energy homeostasis in tumor cells. This route not only supplies ATP but
also provides an additional opportunity to generate reduced
nucleotides. b-Oxidation is the chemical breakdown of fatty
acids that uses NADþ and FAD2þ precursors to produce one
NADH and one FADH2 for every two carbons removed
(12). These reduced products can then provide electrons for
transport in any residual OXPHOS-mediated ATP generation in a tumor cell, or may act as antioxidants. However, it
remains unclear if and how glutathione reduction in the
mitochondria might affect oxidation potential in the cytosol (13). Regardless, the accumulating evidence suggests
that some cancers use fatty acid oxidation (FAO) as an
important energy source for survival and proliferation
(14–16). In Fig. 1A, we outline our model for tumor cell
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Reilly and Mak
metabolism in which parallel pathways involved in the
regulation of fatty acid and glucose metabolism are proposed to provide ATP and antioxidants to cancer cells.
Clinical targeting of cancer metabolism
The increased attention provided to the distinctive
characteristics of tumor cell metabolism has led to various clinical interventions (for a recent review, please see
ref. 7). Some of these treatments have focused on disrupting the increased glycolysis in cancer cells. For example, the substrate analog 2-deoxyglucose (2-DG) inhibits
glycolysis at several steps and is an effective cytotoxic
agent (17), suggesting its use as a component of a combination therapy. Metformin is a useful antidiabetes drug
that lowers blood glucose by inhibiting ATP production
in mitochondria (18, 19). This inhibition stimulates
AMP-dependent kinase (AMPK), which in turn leads to
a blockage of gluconeogenesis in the liver. Independent of
this systemic effect, metformin has anticancer properties
at high doses (20, 21). Rapamycin is one of several
inhibitors of mTOR complex 1 (mTORC1; ref. 22), which
is an important effector downstream of phosphoinositide
3-kinase (PI3K). These cytostatic agents function in part
by reducing glucose transport into the cell, thus limiting
glycolysis (23). While some success in halting tumor cell
growth has been achieved using these agents (22), they
have not proved to be a clinical panacea (24). Additional
targets are under investigation, including those that target
fatty acid catabolism.
Functions of CPT1 enzymes
The carnitine palmitoyltransferase 1 (CPT1) family of
proteins plays a critical role in regulation of FAO in normal
cells (25). These enzymes are present on the cytosolic
surface of mitochondria and catalyze the production of
acyl carnitine from acyl-CoA, thereby facilitating lipid transport through the mitochondrial membranes. Acyl carnitine
production represents a critical regulatory step before b-oxidation because the CPT1 enzymes can be inhibited by
malonyl-CoA, a terminal metabolite of the b-oxidation of
many acyl-CoA molecules. Malonyl-CoA, as a fatty acid
precursor, simultaneously drives fatty acid biosynthesis and
impairs fatty acid catabolism, thus regulating the balance of
intracellular fatty acids (26).
The CPT1 family is composed of 3 proteins that show
tissue-specific distribution. CPT1A was first identified in the
liver but is in fact broadly expressed (25). Mutations of the
CPT1A gene have been implicated in hereditary disorders.
In contrast, CPT1B expression is restricted to muscles, and
CPT1C is a brain-specific isoform (25). Unlike CPT1A and
CPT1B, comparatively little is known about the regulation
and function of CPT1C. Indeed, it has not yet been shown
that CPT1C has carnitine-transferase activity in biochemical
assays (27). Instead, the existing evidence suggests that
CPT1C signaling integrates into molecular pathways in the
hypothalamus that regulate food intake (27, 28) and systemic energy use (29).
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CPT1C promotes tumor growth and drug resistance
A role for CPT1C in tumor growth was first revealed by
Zaugg and colleagues (30) in a study showing that CPT1C
expression in an extensive panel of breast cancer xenografts correlated inversely with mTOR activation and
rapamycin sensitivity. The xenograft tumors were analyzed for CPT1C mRNA expression, mTOR activation
status, and rapamycin sensitivity. Not surprisingly,
tumors with increased mTOR activation were also more
likely to be sensitive to rapamycin. What was surprising
was that the rapamycin-sensitive tumors consistently displayed lower CPT1C mRNA expression, whereas rapamycin-resistant tumors were more likely to show high levels
of CPT1C mRNA. This was not the case for either CPT1A
or CPT1B mRNAs. Indeed, among the thousands of genes
analyzed, CPT1C mRNA expression was most strongly
correlated with mTOR activation. The absence of any
known regulatory interaction between mTOR and CPT1C
suggested that mTORC1 and CPT1C act in parallel pathways in cancer cells to achieve a similar outcome. Given
the known activities of CPT1 proteins in catabolic energy
generation in normal cells, it was theorized that CPT1C
might be supplementing the high energy needs of cancer
cells via FAO, and that cancers lacking CPT1C could not
take advantage of this supplementation, and thus were
sensitive to rapamycin. Consistent with this hypothesis,
CPT1C overexpression in vitro in a breast cancer cell line
increased ATP synthesis as well as FAO. Conversely,
siRNA-mediated CPT1C depletion in vitro cooperated
with rapamycin and 2-DG to inhibit cancer cell growth
(30). Intriguingly, CPT1C-deficient embryonic stem cells
and CPT1C-depleted cancer cells were also more sensitive
to other metabolic stresses, including culture under conditions of low glucose or hypoxia (30). This inverse
relationship between CPT1C expression and rapamycin
sensitivity implied that CPT1C might be a possible novel
target for a combined therapy that would disrupt cancer
cell metabolism and kill tumor cells that had become
resistant to drugs targeting the PI3K pathway.
Of course, for CPT1C to reach its potential as an
anticancer target, this normally brain-specific isoform
would have to be expressed in a broad range of cancers
at relatively high frequency. The work of Zaugg and
colleagues, which had already shown the unusual expression of CPT1C in many breast cancers, also showed that
CPT1C mRNA was overexpressed in 13 of 16 lung cancers as compared with levels in paired normal tissues
(30). Our most recent examinations of CPT1C mRNA
expression in a wide array of tumor types have shown
that CPT1C is highly expressed in brain cancers and
several sarcomas (Fig. 1B). Interestingly, hematopoietic
malignancies have the lowest levels of CPT1C mRNA,
perhaps reflecting their greater access to nutrients in the
bloodstream. The fact that aberrant CPT1C expression
occurs in a broad range of tumor types suggests that
CPT1C inhibition may hold promise as a therapy for a
significant proportion of cancers.
Clinical Cancer Research
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Neuroblastoma
Soft-tissue sarcoma
Lung small cell carcinoma
Ewing’s sarcoma
Glioma-astrocytoma
Medulloblastoma
Lung large cell carcinoma
Bone chondrosarcoma
Lung squamous cell carcinoma
Endometrial adenocarcinoma
Malignant melanoma
Osteosarcoma
Breast carcinoma
Esophageal squamous
Thyroid carcinoma
Ovary clear cell carcinoma
Urinary tract transitional cell
Hodgkin’s lymphoma
Mesothelioma
Lung non–small cell carcinoma
Ovarian adenocarcinoma
Lung adenocarcinoma
Prostate adenocarcinoma
Gastric carcinoma
Large intestinal carcinoma
Renal cell carcinoma
Serous ovarian carcinoma
Diffuse large B-cell lymphoma
Pancreatic carcinoma
B-cell lymphoma unspecified
Hepatocellular carcinoma
ALTL
Plasma cell myeloma
Mantle cell lymphoma
Burkitt’s lymphoma
Biliary tract carcinoma
CML
AML
ALBL
Small lymphocytic lymphoma
Anaplastic large cell lymphoma
ALL
CPT1C mRNA expression (RMA)
Published OnlineFirst September 5, 2012; DOI: 10.1158/1078-0432.CCR-11-3281
CPT1C as Anticancer Target
A
Oncogenes
(ras, myc, etc)
ROS
B
8
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Metabolic
stress
AKT
mTORC1
AMPK
Rapamycin
?
Tumor-specific
induction
Antioxidant
production
p53
CPT1C
Glycolysis
FAO
ATP production
Survival/Proliferation
10
CNS malignancies
Sarcomas
Lung malignancies
Non-lung carcinomas
Melanoma
Hematological malignancies
6
4
© 2012 American Association for Cancer Research
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CPT1C regulation
Although CPT1C expression is restricted to the brain in
healthy individuals, it functions as a stress-responsive
gene under a variety of conditions. Specifically, CPT1C
mRNA was found to be upregulated in cell lines from
several different tissues as well as in mice in vivo following
exposure to any one of a number of p53-activating stresses. Reporter assays showed that CPT1C is a direct transcriptional target of p53 and is the only stress-responsive
member of the CPT1 family (30). Our finding that p53
influences a metabolic regulator in normal cells is not
without precedent. Maddocks and Vousden (31) recently
reviewed the growing literature on the role of p53 in
metabolic regulation. In normal cells, p53 functions to
suppress glycolysis and increase FAO and OXPHOS. Thus,
perhaps in a manner parallel to how it responds to DNA
damage, p53 induces the expression of metabolic regulators (as it would DNA repair factors) and only signals
cell death if the crisis cannot be resolved. However, in
lung cancer, CPT1C overexpression is likely not p53
dependent, as p53 is either mutated or present at very
low levels in these malignancies (30). Thus, a p53-independent mechanism, the details of which are still unclear,
seems to regulate CPT1C in cancer cells.
Our evidence also points to positive regulation of CPT1C
expression by AMPK. First, metformin treatment in vitro
upregulates CPT1C mRNA (30). Second, primary fibroblasts from AMPK-deficient mice fail to upregulate CPT1C
when exposed to low glucose and/or hypoxic conditions in
vitro. Moreover, when CPT1C was depleted in tumorigenic
cells and xenografted them into mice, the malignancies that
developed were insensitive to metformin treatment (30).
More recent data suggest that AMPK-mediated enhancement of CPT1C mRNA is mainly p53 dependent (32), but
that at least some of the increase in CPT1C protein associated with AMPK activation is p53 independent. This p53independent regulation may be related to the finding that
AMPK exerts control over CPT1C translation through the
CPT1C 50 UTR (33).
Clinical–Translational Advances
Effective metabolic targeting
Despite initial optimism, the problem of cancer drug
resistance has not been relieved by the emphasis of the last
20 years on more specific oncogene targeting. The genetic
and epigenetic heterogeneity in a tumor allow it to rapidly
mutate, adapt, and inexorably grow. As a result, the last few
years have seen a shift away from drugs designed to inhibit
oncogenic drivers of cancer and toward agents that can
block factors enabling the growth and/or survival of tumor
cells. The targeting of tumor angiogenesis (34, 35), inflammation (36, 37), and immune evasion (38) are all receiving
increasing attention in this respect. The metabolic adaptations displayed by cancer cells are also being viewed with
fresh eyes and evaluated for their potential as drug targets.
Thusfar, the results of monotherapies with agents blocking
metabolic pathways have been disappointing, either
because of high-dose toxicity, as for 2-DG (39, 40), or
because of drug resistance, as for mTOR inhibitors (24).
Combination therapy is therefore a superior strategy for
circumventing these obstacles. As mentioned earlier, the
work on CPT1C has led us to devise a model of cancer cell
metabolism in which FAO and glycolysis function in parallel to provide the cell with energy and antioxidants (refer
to Fig. 1A). We believe that a combined treatment that
simultaneously targets FAO and glycolysis and removes
these supports of cancer cell survival may be a highly
effective therapeutic approach.
CPT1C represents a particularly attractive target to this
end. CPT1 proteins are enzymes and as such should be
relatively easily inhibited by small molecules. Etomoxir is a
small-molecule inhibitor that binds to CPT1 proteins and
inhibits the enzymatic activities of CPT1A and CPT1B in
vitro. However, tests of etomoxir as a treatment of diabetes
or congestive heart failure have yielded disappointing
results (41, 42). Obviously, because no substrate has been
identified for CPT1C and a biochemical assay is thus lacking, progress toward identifying an agent that specifically
targets CPT1C functions has been slow. The evidence that
CPT1C expression allows a tumor cell to overcome metabolic stress should spur researchers to redouble their efforts
to find an effective CPT1C inhibitor. A CPT1C-specific
inhibitor, as opposed to a pan-CPT1 inhibitor, would be
particularly useful as an anticancer agent because CPT1C
expression is restricted to the brain in an otherwise healthy
person. Because most small-molecule drugs cannot easily
pass the blood–brain barrier (43), a CPT1C-specific inhibitor would likely reduce the chance of undesired side effects,
and thus be a safer alternative to approaches that more
broadly inhibit FAO.
Why CPT1C?
With respect to FAO and cancer, an intriguing question
remains, why would tumors activate a brain-specific gene
Figure 1. CPT1C represents a novel metabolic target for cancer therapy. A, CPT1C-directed FAO is a cancer cell–specific metabolic pathway that runs in
parallel to glycolysis. Oncogenes expressed in cancer cells drive the generation of ROS and metabolic adaptations through the parallel PI3K/mTORC1 and
AMPK pathways. These pathways generate antioxidants and ATP that support tumor cell survival and proliferation. In addition, AMPK operates mainly through
p53-dependent transcription to direct CPT1C overexpression in response to metabolic stress. CPT1C then stimulates FAO, which provides additional
antioxidants and ATP that can maintain cancer cell growth. In the absence of p53, CPT1C is induced in cancer cells by undefined, alternative mechanism(s).
Concurrent inhibition of mTORC1-mediated glycolysis and the CPT1C-driven FAO pathway might therefore starve tumor cells of ATP and antioxidants,
decreasing their survival. B, CPT1C mRNA is expressed in a broad range of human malignancies. Data compiled from the cancer cell line encyclopedia (CCLE)
expression analysis (52) show that CPT1C is preferentially expressed in cell lines from central nervous system (CNS) malignancies, sarcomas, and lung
cancers, and is underrepresented in cell lines derived from hematologic malignancies. Plot whiskers reflect 10th- to 90th-percentile coverage of sample data.
RMA, robust multiarray average (53). CML, chronic myelogenous leukemia; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia.
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Published OnlineFirst September 5, 2012; DOI: 10.1158/1078-0432.CCR-11-3281
CPT1C as Anticancer Target
for fulfilling their metabolic needs, particularly when more
broadly expressed family members, namely CPT1A and
CPT1B, are also available but apparently not activated in
cancer cells (44). Presumably, both CPT1A and CPT1B can
also increase FAO (45, 46), so it stands to reason that CPT1C
upregulation must provide a special activity that spurs
tumor growth. The simplest explanation would be that
CPT1C acts on different substrates than CPT1A and CPT1B.
For example, selective fatty acid degradation mediated by
CPT1C activation might provide an advantage for anabolic
tumor cell proliferation. The finding that long-chain polyunsaturated fatty acids, such as arachidonic acid, accumulate in CPT1C-deficient embryonic stem cells also suggests
that CPT1C has distinct substrate specificities (30).
Another possibility is that CPT1C may perform additional roles beyond its involvement in FAO. Work by the Casals
laboratory has furnished evidence that CPT1C is localized
to the endoplasmic reticulum (ER) membrane in neurons
(47), in contrast to the other CPT1 proteins, which are
positioned on the exterior surface of the mitochondria. The
Casals group has also shown that CPT1C functions to
increase intracellular ceramide levels (47, 48), again implying a difference in substrate specificity. This latter observation is puzzling, however, because ceramide is considered a
proapoptotic lipid and thus an unlikely substance that a
cancer cell would accumulate (49). Moreover, the localization of CPT1C on the ER membrane is difficult to reconcile
with the defect in mitochondrial morphology observed in
CPT1C-deficient embryonic stem cells (30). Finally, the
observed roles of CPT1C in appetite control and systemic
energy expenditure (50) suggest that this enigmatic protein
may affect additional pathways that have yet to be
identified.
CPT1C is the only CPT1 family member that is regulated
by p53 (30, 51), but how this property fits into tumor cell
expression of CPT1C is a mystery. Perhaps the activation of
CPT1C by p53 in normal cells subjected to metabolic stress
means that the CPT1C gene is more susceptible to epigenetic
modification upon loss of p53 function. Alternatively,
CPT1C may promote FAO better than either CPT1A or
CPT1B in cells attempting to grow under stress conditions,
such as in an oxidative environment. These issues remain to
be clarified. Practically speaking, however, evidence in
preclinical studies (30) suggests that the targeting of CPT1C,
particularly in combination with mTOR inhibitors, offers
an excellent opportunity to disrupt cancer cell metabolism
and thereby slowing tumor growth.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: T.W. Mak
Development of methodology: T.W. Mak
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): T.W. Mak
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): P.T. Reilly, T.W. Mak
Writing, review, and/or revision of the manuscript: P.T. Reilly, T.W. Mak
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): P.T. Reilly
Study supervision: T.W. Mak
Acknowledgments
The authors thank Russell Jones for helpful discussions and access to
unpublished data, Ines Lohse, Erik Dzneladze, and Susan McCracken for
helpful discussions, and Mary Saunders for scientific editing of the article.
Received August 10, 2012; accepted August 22, 2012; published
OnlineFirst September 5, 2012.
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Clinical Cancer Research
Downloaded from clincancerres.aacrjournals.org on August 3, 2017. © 2012 American Association for Cancer
Research.
Published OnlineFirst September 5, 2012; DOI: 10.1158/1078-0432.CCR-11-3281
Molecular Pathways: Tumor Cells Co-opt the Brain-Specific
Metabolism Gene CPT1C to Promote Survival
Patrick T. Reilly and Tak W. Mak
Clin Cancer Res Published OnlineFirst September 5, 2012.
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