Between Bedside and Bench
Untuning the tumor metabolic machine
Several decades of scientific observations followed by years of basic and now clinical research support the notion that the
metabolic power of tumor cells can provide the long-desired Achilles’ heel of cancer. Yet many questions remain as to what
defines the true metabolic makeup of a tumor and whether well-known factors and pathways involved in metabolic signaling act
as tumor suppressors or oncogenes. In ‘Bedside to Bench’, Kıvanç Birsoy, David M. Sabatini and Richard Possemato discuss
how retrospective studies of diabetic individuals with pancreatic cancer treated with the antidiabetic drug metformin point to a
possible anticancer effect for this drug. Further research will need to discern whether this drug acts at the organismal level or
by directly targeting the power plant of tumor cells. In ‘Bench to Bedside’, Regina M. Young and M. Celeste Simon peruse the
complex function of a key metabolic factor that mediates the cell’s response to low oxygen levels, often found in tumors. This
hypoxia-inducible factor (HIF) comes in two flavors, which can be either tumor promoting or tumor suppressive, depending on the
type of cancer. Because of this, the therapeutic use of HIF inhibitors must proceed with caution. Further defining the relationship
between metabolic regulation of HIF and tumor progression may open up new diagnostic tools and treatments.
The decades-old observation that most
tumors have an elevated glucose consump-
tion rate compared to normal tissues has
received renewed attention in the laboratory
as scientists have come to appreciate that
altered cancer metabolism is a hallmark of
the transformed state1. Metabolic enzymes act
as tumor suppressors, such as the Krebs cycle
enzymes fumarate hydratase and succinate
dehydrogenase, which are mutated in heredi-
tary leiomyomatiosis and renal cell cancer and
in hereditary paraganglioma and pheochro-
mocytoma, respectively2. But mutations can
also confer oncogenic capacity to metabolic
enzymes, such as isocitrate dehydrogenase 1
(IDH1) or IDH2, driving subtypes of brain
cancer and acute myeloid leukemia3.
Unexpectedly, essential metabolic pathways,
such as the serine biosynthetic pathway, are
activated by gene amplification or epigenetic
changes in estrogen receptor–negative breast
cancer, and, surprisingly, essential metabolites
such as glycine are highly consumed in rap-
idly proliferating cancer cells4,5. Finally, well-
established cancer-relevant pathways, such as
the RAS/AKT and mTOR (mammalian target
of rapamycin) cascades, and transcription
factors, including c-myc and HIF, can exert
substantial influence over glucose uptake,
glycolysis, glutaminolysis, fatty acid oxidation
The increased glucose consumption of
tumors has long been exploited by clini-
cians through monitoring tumor uptake of a
fluorine radioisotope of glucose by positron
emission tomography (FDG-PET). This tech-
nique has been used to stage cancer, identify
metastatic sites and monitor treatment effec-
tiveness. Furthermore, the initial degree of
FDG-PET positivity has been correlated to
overall patient outcome across cancer types,
and can vary by cancer subtype7. However, a
full characterization of the metabolic pheno-
type of cancer is still in its initial stages, and
recent basic research findings have not yet
been translated in the clinic. Yet, traditional
chemotherapeutics such as fluorouracil,
methotrexate and gemcitabine indeed inhibit
metabolic enzymes, indicating that targeting
cancer metabolism has clinical potential.
Therapies targeting cancer metabolism
typically target either the metabolic state
of the organism—such as through caloric
restriction8, ketogenic diets9 and modula-
tion of circulating nutrient levels through
enzymes such as asparaginase10—or target the
altered metabolism of the tumor itself—such
as with 2-deoxyglucose, a glucose mimetic
and hexokinase-competitive inhibitor, and
3-bromopyruvic acid, a putative glycolytic
inhibitor, in addition to those mentioned
above11. With the exception of asparaginase,
a drug approved for childhood acute lym-
phoblastic leukemia for decades, the other
approaches have shown promise in limiting
tumor growth in animal models but have con-
siderable hurdles to overcome before becom-
ing approved therapies.
Surprisingly, several recent retrospective
studies have shown in a wide variety of cancer
types the substantial antitumor effects of the
US Food and Drug Administration–approved
antidiabetic drug metformin12,13. For exam-
ple, a retrospective study of diabetic individu-
als with pancreatic cancer, of whom 117 had
received metformin and 185 had not, analyzed
the correlation of metformin use with survival
and showed an increase in 2-year survival
from 15.4% in the control group to 30.1% in
the group taking metformin12. These studies
demonstrate that targeting energy sensing and
use may be a viable anticancer strategy and
provide basic researchers with some clues for
improving upon such strategies, including a
potential role of metformin in directly target-
ing the mitochondria of cancer cells14.
Centuries before biguanides, such as met-
formin, became routinely prescribed for dia-
betes, the French lilac Galega officinalis was
known to contain an agent that reduced the
frequent urination associated with this disease
(Fig. 1)15. It was only in the 1920s that the
active ingredient in the French lilac, guani-
dine, was isolated, nucleating the biguanide
class of drugs. Much of the basic research on
biguanides since then has focused on their
ability to suppress liver gluconeogenesis,
which is believed to occur through activation
■ BeDSIDe To BenCH
Targeting cancer metabolism: a bedside lesson
Kıvanç Birsoy, David M Sabatini & Richard Possemato
Kıvanç Birsoy, David M. Sabatini and Richard
Possemato are at the Whitehead Institute for
Biomedical Research, Cambridge, Massachusetts,
USA, the Department of Biology, Massachusetts
Institute of Technology (MIT), Cambridge,
Massachusetts, USA, the Howard Hughes Medical
Institute, MIT, Cambridge, Massachusetts, USA,
the Broad Institute, Cambridge, Massachusetts,
USA, and The David H. Koch Institute for
Integrative Cancer Research at MIT, Cambridge,
volume 18 | number 7 | july 2012 nature medicine
© 2012 Nature America, Inc. All rights reserved.
Between Bedside and Bench Download full-text
of hepatic AMP-activated protein kinase
(AMPK) signaling16, as biguanides achieve
elevated levels in the liver compared to other
tissues due to the specific expression of the
OCT1 transporter in this organ.
AMPK is itself involved in a cancer-relevant
signaling pathway as a downstream target of
the STK11 tumor suppressor (also known as
LKB1), which is inactivated in Peutz-Jaegers
syndrome, a disease characterized by hamar-
tomatous polyps of the intestine as well as an
overall increased cancer risk17. Interestingly,
most inherited syndromes characterized
by hamartomatous polyps impinge upon
upstream inhibitors of the mTOR complex 1
(mTORC1) pathway18, including tuberous
sclerosis (involving TSC1 or TSC2 mutation),
the PTEN-hamartoma tumor syndromes
(mutation in PTEN), neurofibromatosis (muta-
tion in NF1 or NF2) and perhaps also Birt-
Hogg-Dubé syndrome (mutation in FLCN).
mTORC1, a major intracellular nutrient sensor,
regulates various cellular processes including
protein synthesis, autophagy and ribosomal
biogenesis that collectively affect cell growth,
and mTORC1 activation has been suggested as
a common link for diseases of this type.
Therefore, there is substantial evidence that
activation of AMPK by metformin could exert
an antitumor effect through modulating the
AMPK/mTOR pathways. However, metformin
fails to activate AMPK directly using in vitro
kinase assays19. As such, the prevailing view is
that this drug class indirectly acts on AMPK by
causing an elevated cellular AMP/ATP ratio,
which activates the AMPK pathway. Indeed,
several recent studies showed metformin to
inhibit mitochondrial oxidative phosphoryla-
tion14, a major ATP source in most cells, which
would explain its ability to activate AMPK.
Understanding how the organismal and
cell-autonomous effects of biguanides trans-
late into an anticancer effect will be important
for using these drugs as chemotherapeutics;
however, there are several potential mecha-
nisms explaining the anticancer effects of
metformin. One potential indirect mecha-
nism is the modulation of circulating insulin
levels, as many tumors are driven by insulin
receptor signaling, and such tumors can be
sensitive to metformin treatment20. But, in
the retrospective study by Sadeghi et al.12,
metformin exerts an antitumor effect on
pancreatic cancer regardless of concomitant
insulin treatment. As such, the organismal
effects of metformin on insulin signaling, as
well as other potential organismal effects, will
require further evaluation.
In support of a direct effect on mitochon-
drial oxidative phosphorylation in cancer
cells, metformin has been shown to inhibit
cancer cell proliferation in vitro and in vivo
in numerous studies. However, it does so in
vitro only at high doses that might not be
achievable in vivo in a tumor, arguing that
the observed in vivo effect is actually indi-
rect. Furthermore, the glycolytic nature of
tumors argues against the efficacy of a mito-
chondrial inhibitor, as cancer cells might
derive most of their energy from glycolysis.
Nevertheless, recent studies have shown that
substantial mitochondrial glucose oxidation
occurs in glioblastoma models in vivo and
in vitro21. Whereas the importance of mito-
chondrial glucose oxidation to the tumor has
yet to be fully investigated, its suppression
may be linked to increased reactive oxygen
species production, a loss of mitochondrial
membrane potential, energy crisis due to
ATP depletion, decreased citric acid cycle
function or activation of the AMPK pathway
directly in the tumor. Therefore, a thorough
analysis of the metabolic state of tumors in
animal models or in patients with cancer
treated with metformin will be necessary
for understanding whether metformin has
a direct effect on cancer cells and whether
this effect underlies the observed clinical
It is unclear whether the efficacy of met-
formin will be limited to individuals with
both diabetes and cancer. Ongoing prospec-
tive studies using metformin in nondiabetics
will elucidate whether the anticancer effects
of metformin also occur in individuals with
normal glucose homeostasis. Regardless, the
current successes in the clinic are a signal to
investigators that mitochondrial inhibition,
be it in the liver or the tumor, may inhibit
tumor growth and should provide guidance
for future laboratory research.
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
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Direct antitumoral effect?
Figure 1 Potential effects of metformin on tumor growth. Metformin is of the biguanide class of
compounds, modeled after guanidine derivatives first isolated from the French lilac G. officinalis.
This drug has a well-established role in suppressing hepatic gluconeogenesis, thereby ameliorating
hyperglycemia in individuals with type 2 diabetes, but new studies are beginning to unearth a role for
metformin in suppressing cancer progression. It is still unclear whether this is by direct action of the
drug on the cancer cells themselves or through an indirect effect on organismal metabolism.
nature medicine volume 18 | number 7 | july 2012
© 2012 Nature America, Inc. All rights reserved.