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Cancer Cell Metabolism
Nadi Wickramasekera, Ph.D. ! Dept. of Pharmacology and Therapeutics (L4-107) ! [email protected]
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Acquired Abilities for Cancer Progression: Cancer Hallmarks 2000 vs 2011
An Emerging Hallmark: Reprogramming Energy Metabolism
Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:6462
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Lecture Outline
Discuss and review the biochemical pathways involved in anaerobic and aerobic production of ATP !How is cancer-cell metabolism different?. Warburg theory of cancer or "Warburg hypothesis -1924” !Cancer cell metabolism: Warburg and beyond. The possible drivers and advantages of the altered metabolism of cancer cells ! Linking oncogenes and tumor suppressor's to tumor cell metabolism ! Inhibiting the high glycolytic activity in cancer cells for therapeutic purposes !Mitochondria in cancer cells !Application and integration of tools to study tumor metabolism
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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 !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
Metabolism (Overview)
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Map of Metabolic Pathways
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Basic Chemical Reactions Underlying Metabolism
Catabolism and Anabolism !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)6
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Metabolism Composed of Catabolic and Anabolic Reactions
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BioenergeticsCell Energy ATP is the main energy currency of cells !Formation of ATP Degradation of glucose and glycogen -Glycolysis Oxidative formation of ATP - Oxidative phosphorylation Anaerobic pathways - Do not involve O2 - Glycolysis
!Aerobic pathways - Require O2 - Oxidative phosphorylation !
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Basic Steps Involved
Glycolysis
Krebs Cycle
Electron Transport System
Acetyl CoA Formation
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AnaerobicAerobic
ATP Generating Metabolic Pathways
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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
Energy yield: 2 ATP and 2 NADH
Glucose Pyruvic acid
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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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Pyruvate
Glucose
CYTOSOL
No O2 present Fermentation
Ethanol or
lactate
Acetyl CoA
MITOCHONDRION
O2 present Cellular respiration
Citric acid cycle
Anaerobic Respiration
Aerobic Respiration
Fate of Pyruvate
ATP2acidlactic2glucose +→
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Transition Reaction
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Krebs Cycle (Citric Acid Cycle)
Transition Reaction
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Oxidative Phosphorylation
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ATP Generating Metabolic Pathways
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Overall ATP Production
Electron Transport System 34 Citric Acid Cycle 2 Glycolysis 2 SUBTOTAL 38 NADH Transport into Mitochondrion* -2 TOTAL 36
(-2) some ATP is used to pump NADH across membrane so ~ 36 ATP !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
about 40% efficiency
ATP
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The high-energy ATP molecules store 7.3 kcal of energy per mole
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What Feeds a Tumor?
NCI web site 20
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How is Cancer Cell Metabolism different ?
21Matthew G. Vander Heiden, Science Webinar.
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The Warburg Theory of Cancer or "Warburg hypothesis"
Dr. Otto H. Warburg ( 1883 – 1970)
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. 22
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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
What is the Warburg Effect?
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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)
Acquired Abilities for Cancer Progression: Cancer Hallmarks 2000 vs 2011
An Emerging Hallmark: Reprogramming Energy Metabolism
Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell 2011, 144:64624
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Matthew G. Vander Heiden et al, Science, 2009
Tumor Metabolism: How is it Different?
Glycolysis
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Warburg Effect
QO2: oxygen consumed/ml QMO2: lactic acid produced aerobically /ml
QMN2: lactic acid produced anaerobically /ml
Science 1956;124: (3215) 269-‐70
The higher the malignancy, the greater the fermentation and the smaller the respiration
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Nature Rev Cancer 2004;4:891-‐9Low malignancy High Malignancy
Higher Glucose Uptake Correlates With More Aggressive Phenotypes and Poorer Clinical Outcomes
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Cancer: Principles & Practice of Oncology 9th Edition
Clinical FDG-PET Scanning Exploits Cancer Metabolism
Matthew G. Vander Heiden et al, Science, 2009
Cancer cells must compensate for the ~18-fold lower efficiency of ATP production afforded by glycolysis relative to mitochondrial oxidative phosphorylation !Cancer cells upregulate glucose transporters, which substantially increases glucose import into the cytoplasm
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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 31
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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 ! 32
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Cell Proliferation Requires the Conversion of Nutrients into Biomass
Non-proliferating Cells !NUTRIENTS N
UT
RI
ES
TATP
Proliferating Cancer Cells
NU
TRI
ES
T!NUTRIENTS
!NUTRIENTS
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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 Press34
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Most of the Increased Nutrient Uptake in Cancer is Used to Support Biosynthesis
Matthew G. Vander Heiden. Nat Rev Drug Discov. 2011 35
10%
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Normal differentiated cells Oxidative Phosphorylation
CO2Proliferating cells Aerobic Glycolysis
Pyruvate Kinase (PK-M2 ) Activity is Regulated by cell Growth Signals and Promotes Anabolic Metabolism
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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
!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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The tumor microenvironment selects for altered metabolism
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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 Research40
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OXPHOS In
Mitochondria
OXPHOS-‐ Oxidative Phosphorylation41
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Linking Oncogenes and Tumor Suppressor's to Tumor Cell Metabolism
42Cancer 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 Research44
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Science 2006;312:1650-‐4 46
p53 and Mitochondrial Respiration
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p53 and Mitochondrial Respiration
Science 2006;312:1650-4
HCT116
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Science 2006;312:1650-448
p53 and Mitochondrial Respiration
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Shen L et al. Clin Cancer Res 2012;18:1561-1567©2012 by American Association for Cancer Research
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P53 Regulates Cellular Metabolism
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Acta Pharmacologica Sinica (2010) 31: 1208–1212
Wild-type p53 and Mutant-‐ p53 have Opposing Roles in Cellular Metabolism
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Summary: Factors Affecting Cancer Metabolism
TW Mak et al., Nat Rev Cancer, 2011 51
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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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53Oncogene (2006) 25, 4633–4646, J Bioenerg Biomembr. 2012 Feb;44(1):17-‐29
Glycolytic Inhibitors With Anticancer Activity
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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 Press54
Mitochondrial Function During Oncogenesis
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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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Reprogramming energy metabolism is an an emerging hallmark in deregulation of cell proliferation !
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
!~ 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
!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
!These changes are a result of transcription factors such as HIF and p53
!Drugs currently in development/clinical trials to disrupt aerobic glycolysis in cancer cells, are focused on blocking glucose uptake, or inhibiting specific glycolytic enzymes
!Cancer metabolism can cooperated into signal transduction, and serve as a route to study cancer biology
!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
Summary
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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.
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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 !