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Cancer Cell Metabolism
Nadi Wickramasekera, Ph.D.
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Dept. of Pharmacology and Therapeutics (L4-107)
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[email protected]
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An Emerging Hallmark: Reprogramming Energy Metabolism
Acquired Abilities for Cancer Progression: Cancer
Hallmarks 2000 vs 2011
Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646
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Lecture Outline
Discuss and review the biochemical pathways involved in anaerobic and
aerobic production of ATP
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How is cancer-cell metabolism different?. Warburg theory of cancer or
"Warburg hypothesis -1924”
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Cancer cell metabolism: Warburg and beyond. The possible drivers and
advantages of the altered metabolism of cancer cells
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Linking oncogenes and tumor suppressor's to tumor cell metabolism
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Inhibiting the high glycolytic activity in cancer cells for therapeutic purposes
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Mitochondria in cancer cells
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Application and integration of tools to study tumor metabolism
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Metabolism (Overview)
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Metabolism: !
Collection of controlled intracellular biochemical reactions that
convert nutrients and endogenous molecules to energy and
matter (proteins, nucleic acids, and lipids) that sustain life
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A sequence of chemical reactions, where the product of one
reaction serves as a substrate for the next, is called a metabolic
pathway or biochemical pathway !
Most metabolic pathways take place in specific regions of the
cell
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Map of Metabolic
Pathways
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Basic Chemical Reactions Underlying Metabolism
Catabolism and Anabolism
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Two major classes of metabolic reactions !
Catabolic pathways • Break larger molecules into smaller products • Exergonic (release energy) Anabolic pathways • Synthesize large molecules from the smaller
products of catabolism • Endergonic (require more energy than they
release)
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Metabolism Composed of Catabolic and Anabolic Reactions
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Bioenergetics
Cell Energy
ATP is the main energy currency of cells
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Formation of ATP
Degradation of glucose and glycogen
-Glycolysis
Oxidative formation of ATP
- Oxidative phosphorylation
Anaerobic pathways
- Do not involve O2
- Glycolysis
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Aerobic pathways
- Require O2
- Oxidative phosphorylation
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Basic Steps Involved
1
Glycolysis
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Acetyl CoA Formation
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Krebs Cycle
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Electron Transport System
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ATP Generating Metabolic Pathways
Aerobic
Anaerobic
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Glycolysis
Glycolysis (“splitting of sugar”) breaks down glucose into two molecules
of pyruvate
Occurs in the cytoplasm and has two major phases
– Energy investment phase – Energy payoff phase Occurs whether or not O2 is present
Glycolysis harvests chemical energy by oxidizing glucose to pyruvic acid
The oxidation of glucose to pyruvic acid produces ATP and NADH
Pyruvic
acid
Glucose
Energy yield: 2 ATP and 2 NADH
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Balance Sheet for Glycolysis
Input
1 Glucose
2 ADP + Pi
2 NAD+
Output
2 Pyruvate
2 ATP
2 NADH
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Glucose
Fate of
Pyruvate
CYTOSOL
Pyruvate
Anaerobic Respiration
Aerobic Respiration
O2 present
Cellular respiration
No O2 present
Fermentation
MITOCHONDRION
Ethanol
or
lactate
glucose → 2 lactic acid + 2 ATP
Acetyl CoA
Citric
acid
cycle
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Transition Reaction
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Transition Reaction
Krebs Cycle (Citric Acid Cycle)
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Oxidative Phosphorylation
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ATP Generating Metabolic Pathways
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Overall ATP Production
Electron Transport System
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Citric Acid Cycle
2
Glycolysis
2
SUBTOTAL
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NADH Transport into Mitochondrion*
TOTAL
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-2
(-2) some ATP is used to pump NADH across membrane so ~ 36 ATP
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The high-energy ATP molecules store 7.3 kcal of energy per mole
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Net ATP Yield
34 to 36 molecules ATP for every
glucose molecule
ATP
about 40% efficiency
The high-energy ATP molecules store 7.3 kcal of energy per mole
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What Feeds a Tumor?
NCI web site
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How is Cancer Cell Metabolism different ?
Matthew G. Vander Heiden, Science Webinar.
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The Warburg Theory of Cancer or "Warburg hypothesis"
Warburg hypothesis 1924
“Cancer, above all other diseases,
has countless secondary causes.
But, even for cancer, there is only
one prime cause. Summarized in a
few words, the prime cause of cancer
is the replacement of the respiration
of oxygen in normal body cells by a
fermentation of sugar… " -- Dr. Otto
H. Warburg in Lecture On the Origin of Cancer Cells. Otto Warburg
Science 24 February 1956: 309-314.
Dr. Otto H. Warburg ( 1883 – 1970) 22
What is the Warburg Effect?
Observation that most cancer cells
predominantly produce energy through a high
rate of glycolysis followed by lactic acid
fermentation, rather than through oxidative
phosphorylation in the mitochondria
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An Emerging Hallmark: Reprogramming Energy Metabolism
Acquired Abilities for Cancer Progression: Cancer
Hallmarks 2000 vs 2011
The uncontrolled growth and division of cancer
cells relies not only on the deregulation of cell
proliferation, but also on the reprogramming of
cellular metabolism, including increased aerobic
glycolysis (known as the Warburg effect)
Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:646
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Tumor Metabolism: How is it Different?
Glycolysis
Matthew G. Vander Heiden et al, Science, 2009 25
Warburg Effect
The higher the malignancy, the greater the fermentation and the smaller the respiration
QO2: oxygen consumed/ml QMO2: lactic acid produced aerobically /ml QMN2: lactic acid produced anaerobically /ml
Science 1956;124: (3215) 269-­‐70
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Higher Glucose Uptake Correlates With More Aggressive
Phenotypes and Poorer Clinical Outcomes
Low malignancy
Nature Rev Cancer 2004;4:891-­‐9
High Malignancy
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Clinical FDG-PET Scanning Exploits
Cancer Metabolism
Cancer cells must compensate for the ~18-fold lower efficiency of ATP production
afforded by glycolysis relative to mitochondrial oxidative phosphorylation
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Cancer cells upregulate glucose transporters, which substantially increases glucose
import into the cytoplasm
Cancer: Principles & Practice of Oncology 9th Edition Matthew G. Vander Heiden et al, Science, 2009 28
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Cancer Cell Metabolism:
Warburg and Beyond
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The Possible Drivers, Advantages, and Potential Liabilities of
the Altered Metabolism of Cancer Cells
Hsu PP et al. Cell. 2008 Sep 5;134(5):703-­‐7
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The Possible Advantages of the Altered Metabolism
of Cancer Cells
Altered Metabolism Provides Substrates for Biosynthetic Pathways !
Aerobic glycolysis is about 100 times faster than oxidative-­‐ phosphorylation in the mitochondria !
Increased glycolysis allows the diversion of glycolytic intermediates into various biosynthetic pathways !
Facilitates the biosynthesis of the macromolecules and organelles required for assembling new cells !
Ensures that cancer cells have a ready supply of the building blocks needed for macromolecule synthesis !
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Cell Proliferation Requires the Conversion of Nutrients into Biomass
Non-proliferating Cells
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NUTRIENTS
E
N
S
I R
T
U
T
ATP
Proliferating Cancer Cells
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NUTRIENTS
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NUTRIENTS
EN TU
S
I
T
R
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Glucose and Glutamine Feed Cell Growth and
Proliferation
Dang C V Genes Dev. 2012;26:877-890
Copyright © 2012 by Cold Spring Harbor Laboratory Press
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Most of the Increased Nutrient Uptake in Cancer is Used to Support Biosynthesis 10%
Matthew G. Vander Heiden. Nat Rev Drug Discov. 2011 35
Pyruvate Kinase (PK-M2 ) Activity is Regulated by cell
Growth Signals and Promotes Anabolic Metabolism
CO2
Normal differentiated cells
Oxidative Phosphorylation
Proliferating cells
Aerobic Glycolysis
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PKM2 Regulates an Anabolic Program to Support Cancer Cell
Proliferation
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The Possible Drivers of the Altered
Metabolism of Cancer Cells
The tumor microenvironment selects for altered
metabolism
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Hypotheses: Hypoxic conditions (A decrease in ambient O2
availability and levels) Persistent metabolism of glucose to lactate even in aerobic conditions is
an adaptation to intermittent hypoxia in pre-malignant lesions !
Upregulation of glycolysis leads to microenvironmental acidosis
requiring evolution to phenotypes resistant to acid-induced cell toxicity !
Subsequent cell populations with upregulated glycolysis and acid
resistance have a powerful growth advantage, which promotes
unconstrained proliferation and invasion
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Hypoxia-Inducible Transcription Factor (HIF)
Tumors outgrows the diffusion limits of its local blood supply,
leading to hypoxia and stabilization of the hypoxia-inducible
transcription factor, HIF
HIF-1 is critical to glycolysis, induces nearly all enzyme
transcription
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HIF-1 Pathway
Meijer T W et al. Clin Cancer Res 2012;18:5585-5594
©2012 by American Association for Cancer Research
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OXPHOS In Mitochondria
OXPHOS-­‐ Oxidative Phosphorylation
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Linking Oncogenes and Tumor Suppressor's to Tumor Cell
Metabolism
Cancer Cell. 2008 Jun;13(6):472-­‐82
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Cancer Cell. 2008 Jun;
13(6):472-­‐82
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Signalling and Transcriptional Machinery that Regulate Metabolism:
PI3K/Akt Pathway
Cantor J R , and Sabatini D M Cancer Discovery
2012;2:881-898
©2012 by American Association for Cancer Research
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p53 and Mitochondrial Respiration
Science 2006;312:1650-­‐4
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p53 and Mitochondrial Respiration
HCT116
Science 2006;312:1650-4
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p53 and Mitochondrial Respiration
Science 2006;312:1650-4
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P53 Regulates Cellular Metabolism
Shen L et al. Clin Cancer Res 2012;18:1561-1567
©2012 by American Association for Cancer Research
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Wild-type p53 and Mutant-­‐ p53 have Opposing Roles in Cellular Metabolism Acta Pharmacologica Sinica (2010) 31: 1208–1212
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Summary: Factors Affecting Cancer Metabolism
TW Mak et al., Nat Rev Cancer, 2011
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Glycolytic Inhibitors With Anticancer Activity
Oncoene 2006; 25:4633-46 , J Bioegnerg Biomembr 2007; 39:267-74
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Glycolytic Inhibitors With Anticancer Activity
Oncogene (2006) 25, 4633–4646, J Bioenerg Biomembr. 2012 Feb;44(1):17-­‐29
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Mitochondrial Function During Oncogenesis
The possible effects of loss of supercomplex organization on mitochondrial function during
oncogenesis.
Gasparre G et al. Cold Spring Harb Perspect Biol
2013;5:a011411
©2013 by Cold Spring Harbor Laboratory Press
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Application and Integration of Tools to Study Tumor Metabolism
Cantor J R , and Sabatini D M Cancer Discovery
2012;2:881-898
©2012 by American Association for Cancer Research
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Summary Reprogramming energy metabolism is an an emerging hallmark in deregulation of cell proliferation
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The Warburg effect, or aerobic glycolysis, is the observation that most cancer cells produce energy through a high rate of
glycolysis followed by lactic acid fermentation, even in the presence of oxygen
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~ 90 years after Warburg’s idea, aerobic glycolysis indeed play important roles in cancer biology
Using glucose analog FDG, PET can pinpoint the location of cancer cells
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Changes in the tumor microenvironment, oncogene activation, transcription rate of enzymes and transporters involved in
glycolysis and oxidative metabolism are believed to push cancer cells into adopting aerobic glycolysis
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These changes are a result of transcription factors such as HIF and p53
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Drugs currently in development/clinical trials to disrupt aerobic glycolysis in cancer cells, are focused on blocking glucose
uptake, or inhibiting specific glycolytic enzymes
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Cancer metabolism can cooperated into signal transduction, and serve as a route to study cancer biology
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Solid tumor is heterogeneous, and each cancer cell is a function of oxygen, glucose, pH, HIF-1, and p53…, which make
targeting therapy more challenging
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References
Recommended Reading:
1. Tumor cell metabolism: cancer's Achilles' heel. Kroemer G, Pouyssegur J.Cancer
Cell. 2008 Jun;13(6):472-82.
2. Understanding the Warburg effect: the metabolic requirements of cell proliferation.
Vander Heiden MG, Cantley LC, Thompson CB. Science. 2009 May 22;324(5930):
1029-33.
3. On the origin of cancer cells. WARBURG O. Science. 1956 Feb 24;123(3191):309-14.
Required Reading:
1. Cancer cell metabolism: Warburg and beyond. Hsu PP, Sabatini DM.Cell.
2008 Sep 5;134(5):703-7.
2. p53 and metabolism. Vousden KH, Ryan KM. Nat Rev Cancer. 2009 Oct;
9(10):691-700.
3. p53 regulates mitochondrial respiration. Matoba S, Kang JG, Patino WD,
Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM. Science.
2006 Jun 16;312(5780):1650-3.
4. Regulation of cancer cell metabolism. Cairns RA, Harris IS, Mak TW. Nat
Rev Cancer. 2011 Feb;11(2):85-95
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