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ADDICTION OF CANCER TO GLUCOSE

Dr. Syed Shoeb Iqbal Razvi


Research Associate
MS Research Foundation
India.

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SEM Uncontrolled division of Breast cancer cells.

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Image: Annie Cavanagh 2006
HALLMARKS OF CANCER: ADAPTATIONS TO EVADE DEATH

Cell, Vol. 100, 57–70, January 7, 2000


TUMOR MICROENVIRONMENT PLAYS AN IMPORTANT ROLE

• Nutrient source
– Glucose
– Amino Acids
– Oxygen
• Growth factors
• Structural support
– Extracellular Matrix
• Cell-Cell interactions
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Nature Vol 455; 18 September 2008


GLUCOSE IS THE BODY’S MAJOR NUTRIENT AND ENERGY SOURCE

• The human body exquisitely maintains the


level of circulating glucose in the range of 5
mM.
• Nearly all carbohydrates ingested in the diet
are converted to glucose following transport
to the liver.
• Breakdown of dietary or cellular proteins
generates carbon atoms that can be utilized
for glucose synthesis via gluconeogenesis.
• Additionally, skeletal muscle and
erythrocytes provide lactate that can be
converted to glucose via gluconeogenesis.
• Maintenance of glucose homeostasis is of
paramount importance to the survival of the
human organism. 5

The same could be said of cancer....


CELLS ALTER THEIR METABOLISM IN RESPONSE TO STIMULI

• Microbes and cells from multicellular organisms


have similar metabolic profiles under similar
environmental conditions.
• During proliferation, these organisms both
metabolize glucose primarily through
glycolysis, excreting large amounts of carbon in
the form of ethanol, lactate, or another organic
acid.
• When starved of nutrients, both rely primarily
on oxidative metabolism.
• Evolutionarily, there is an advantage to
oxidative metabolism during nutrient limitation
and an advantage in glycolysis during cell
proliferation.
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Matthew G. Vander Heiden, et al. Science 324, 1029 (2009)


AEROBIC GLYCOLYSIS: THE WARBURG EFFECT

• In the presence of O2, nonproliferating tissues first metabolize glucose to pyruvate


via glycolysis and then completely oxidize most of that pyruvate in the
mitochondria to CO2 during the process of oxidative phosphorylation (OxPhos).
• Because oxygen is required as the final electron acceptor to completely oxidize the
glucose, oxygen is essential for this process. When oxygen is limiting, cells can
redirect the pyruvate generated by glycolysis away from mitochondrial OxPhos by
generating lactate.
• Lactate production allows glycolysis to continue (by cycling NADH back to
NAD+), but results in minimal ATP production when compared with OxPhos.
• Otto Warburg observed that cancer cells tend to convert most glucose to lactate
regardless of whether oxygen is present (aerobic glycolysis).
• This property is shared by normal proliferative tissues.
• Mitochondria remain functional and some oxidative phosphorylation continues in
both cancer cells and normal proliferating cells.
• Aerobic glycolysis is less efficient than OxPhos or generating ATP. The cells make
up for this by consuming more glucose. 7

Matthew G. Vander Heiden, et al. Science 324, 1029 (2009)


HOW CANCER CELLS REPROGRAM THEIR METABOLISM

• Metabolic cross-talk allows for both


NADPH production and Ac-CoA flux
for lipid synthesis.
• These metabolic pathways can be
influenced by cell proliferation
signaling pathways.
• Activation of growth factor receptors
leads to downstream signaling cascade
activation.
• PI3K/Akt activation stimulates glucose
uptake and flux through the early part of
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glycolysis.
Vander Heiden, et al. Science 324, 1029 (2009)
• Tyrosine kinase signaling negatively
regulates flux through the late steps
of glycolysis, making glycolytic
intermediates available for
macromolecular synthesis as well as
supporting NADPH production.
• Myc drives glutamine metabolism,
which also supports NADPH
production.
• LKB1/AMPK signaling and p53
decrease metabolic flux through
glycolysis in response to cell stress.
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Vander Heiden, et al. Science 324, 1029 (2009)


TARGETING METABOLISM FOR CANCER THERAPY

• Small molecule drugs that disrupt glucose


metabolism or decrease glucose uptake by
tumors could provide anti-cancer therapy.
We can visualize altered glucose
metabolism in tumors by 18Fdeoxyglucose
positron emission tomography (FDG-PET).
The ability to inhibit tumor FDG uptake
correlates with tumor Regressio.
• Seen here: Malignant sarcoma
(gastrointestinal stromal tumor) before and
after therapy with a tyrosine kinase
inhibitor (sunitinib). 10

Matthew G. Vander Heiden, et al. Science 324, 1029 (2009)


GLYCOLYSIS CAN PROMOTE RESISTANCE TO CANCER THERAPY

• Glycolysis provides the metabolites


and energy for DNA repair and
chemotherapy drug
inactivation/detoxification.
• Glycolysis can provide ATP/NAD+
for DNA repair.
• Glycolysis, pentose phosphate
pathway and glutaminolysis can
also provide NADPH.
• These mechanisms can potentially
contribute to resistance of the
cancer to therapy.
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Cell. Mol. Life Sci. 65 (2008) 3981 – 3999


TUMORS ARE NOT AS ADDICTED TO GLUCOSE AS PREVIOUSLY
THOUGHT??
• The research, led by senior authors Heather Christofk and Bill Lowry from Eli and Edythe Broad Center
of Regenerative Medicine and Stem Cell Research at UCLA have discovered that squamous cell skin
cancers do not require increased glucose to power their development and growth, contrary to a long-held
belief about cancer metabolism.
• The team studied the progression of squamous cell skin cancer in animal models whose hair follicle stem
cells had been genetically modified to limit their glucose consumption.
• Specifically, they de-activated a gene called lactate dehydrogenase-a, which catalyzes the final step in a
cell’s process of converting glucose to lactate.
• Deactivating this gene prevented this final step from taking place, which in turn caused the cells to
dramatically reduce their glucose consumption.
• The change had no effect on cancer incidence or progression. When faced with insufficient glucose for
their increased needs, the cancer cells in this model simply altered their metabolism to derive energy from
the amino acid glutamine. 12

(A. Flores et.al.,2019)


IN FURTHER….

• Non-small lung carcinoma: The two drugs, MLN128 and CB-839, individually
target the metabolism of key nutrients glucose and glutamine, respectively,
prohibiting the cancer from switching metabolic gears between glucose (a simple
sugar) and glutamine (an amino acid) to tap vital sources of energy. This switch
enables the cancer cells to adapt their metabolism and evade treatments. (Milica
Momcilovic et.al, 2018)
• It is possible that dual inhibition of both Ldh activity and glutamine uptake or
glutaminase could potentially starve tumors by circumventing their metabolic
flexibility, and this will be the focus of effort going forward. (A. Flores
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et.al.,2019)
METABOLIC TARGETS OF CANCER STEM CELLS.

• Specifically, in models in which cancer


stem cells are more reliant on glycolysis, 3-
bromopyruvate (3BP) or dichloroacetate
(DCA) can reprogram the metabolism of
these cells and sensitize them to
chemotherapeutic agents.
• In cancer stem cells that exhibit increased
oxidative phosphorylation (OXPHOS),
inhibition of mitochondrial respiration by
metformin, phenformin, rotenone,
oligomycin or antimycin can trigger
apoptosis.
• Inhibition of fatty acid oxidation (FAO) by
etomoxir, which inhibits the carnitine-
dependent transporter 1 (CPT1), leads to
sensitization of cancer stem cells to
apoptosis-inducing agents. 14

Disease Models & Mechanisms (2018) 11, dmm033464. doi:10.1242/dmm.033464


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