Cancer Cell Metabolism

Nadi Wickramasekera, Ph.D. ! Dept. of Pharmacology and Therapeutics (L4-107) ! Nadi.wickramasekera@RoswellPark.org

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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

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

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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2

3

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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

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

What  Feeds  a  Tumor?

NCI  web  site 20

How is Cancer Cell Metabolism different ?

21Matthew  G.  Vander  Heiden,  Science  Webinar.

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

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

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

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

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

Most  of  the  Increased  Nutrient  Uptake  in  Cancer  is  Used  to  Support  Biosynthesis  

Matthew  G.  Vander  Heiden.  Nat  Rev  Drug  Discov.  2011   35

10%

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

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

OXPHOS  In  

Mitochondria

OXPHOS-‐  Oxidative  Phosphorylation41

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

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

p53 and Mitochondrial Respiration

Science 2006;312:1650-4

HCT116

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Science 2006;312:1650-448

p53 and Mitochondrial Respiration

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

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

53Oncogene  (2006)  25,  4633–4646,  J  Bioenerg  Biomembr.  2012  Feb;44(1):17-‐29

Glycolytic Inhibitors With Anticancer Activity

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

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 !