Cancer Cell Metabolism

Transcription

1 Cancer Cell Metabolism Nadi Wickramasekera. Ph.D. Dept. of Pharmacology and Therapeutics (L4-107) 1

2 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 2

3 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 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 3

4 Metabolism (Overview) 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 4

5 Map of Metabolic Pathways 5

6 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

7 Metabolism Composed of Catabolic and Anabolic Reactions 7

8 Bioenergetics Cell 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 O 2 - Glycolysis Aerobic pathways - Require O 2 - Oxidative phosphorylation 8

9 Basic Steps Involved 1 Glycolysis 2 Acetyl CoA Forma8on 3 Krebs Cycle 4 Electron Transport System 9

10 ATP Generating Metabolic Pathways Anaerobic Aerobic 10

11 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 O 2 is present Glycolysis harvests chemical energy by oxidizing glucose to pyruvic acid The oxidation of glucose to pyruvic acid produces ATP and NADH Glucose Pyruvic acid Energy yield: 2 ATP and 2 NADH 11

12 Balance Sheet for Glycolysis Input 1 Glucose 2 ADP + P i 2 NAD + Output 2 Pyruvate 2 ATP 2 NADH 12

13 Fate of Pyruvate Glucose CYTOSOL Anaerobic Respira=on No O 2 present Fermentation Pyruvate Aerobic Respira=on O 2 present Cellular respiration Ethanol or lactate Acetyl CoA MITOCHONDRION Citric acid cycle 13

14 Transi=on Reac=on 14

15 Transi8on Reac8on Krebs Cycle (Citric Acid Cycle) 15

16 Oxidative Phosphorylation 16

17 ATP Generating Metabolic Pathways 17

18 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 18

19 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 19

20 What Feeds a Tumor? NCI web site 20

21 How is Cancer Cell Metabolism different? MaBhew G. Vander Heiden, Science Webinar. 21

22 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 Dr. O4o H. Warburg ( ) On the Origin of Cancer Cells. Otto Warburg Science 24 February 1956:

23 What is the Warburg Effect? O b s e r v a t i o n t h a t m o s t c a n c e r c e l l s predominantly produce energy through a high rate of glycolysis followed by lactic acid fermentation, rather than through oxidative phosphorylation in the mitochondria. 23

24 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 24

25 Tumor Metabolism: How is it Different? Glycolysis MaBhew G. Vander Heiden et al, Science,

26 Warburg Effect The higher the malignancy, the greater the fermentahon and the smaller the respirahon QO 2 : oxygen consumed/ml Q M O2: lachc acid produced aerobically /ml Q M N2: lachc acid produced anaerobically /ml Science 1956;124: (3215)

27 Higher Glucose Uptake Correlates With More Aggressive Phenotypes and Poorer Clinical Outcomes Low malignancy Nature Rev Cancer 2004;4:891-9 High Malignancy 27

28 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 Cancer cells upregulate glucose transporters, which substantially increases glucose import into the cytoplasm MaBhew G. Vander Heiden et al, Science, 2009 Cancer: Principles & Prac/ce of Oncology 9th Edi8on 28

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30 Cancer Cell Metabolism: 30

31 The Possible Drivers, Advantages, and Potential Liabilities of the Altered Metabolism of Cancer Cells Hsu PP et al. Cell Sep 5;134(5):

32 The Possible Advantages of the Altered Metabolism of Cancer Cells Altered Metabolism Provides Substrates for Biosynthe=c Pathways Aerobic glycolysis is about 100 Hmes faster than oxidahve- phosphorylahon in the mitochondria Increased glycolysis allows the diversion of glycolyhc intermediates into various biosynthehc 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

33 Cell Proliferation Requires the Conversion of Nutrients into Biomass Non-proliferating Cells NUTRIENTS E S I N T U T R ATP Proliferating Cancer Cells NUTRIENTS NUTRIENTS EN T U S I T R 33

34 Glucose and Glutamine Feed Cell Growth and Proliferation Dang C V Genes Dev. 2012;26: Copyright 2012 by Cold Spring Harbor Laboratory Press

35 Most of the Increased Nutrient Uptake in Cancer is Used to Support Biosynthesis 10% MaBhew G. Vander Heiden. Nat Rev Drug Discov

36 Pyruvate Kinase (PK-M2 ) Activity is Regulated by cell Growth Signals and Promotes Anabolic Metabolism CO 2 Normal differentiated cells Oxidative Phosphorylation Proliferating cells Aerobic Glycolysis 36

37 PKM2 Regulates an Anabolic Program to Support Cancer Cell Proliferation 37

38 The Possible Drivers of the Altered Metabolism of Cancer Cells The tumor microenvironment selects for altered metabolism Hypotheses: Hypoxic conditions (A decrease in ambient O 2 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 38

39 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 39

40 HIF-1 Pathway Meijer T W et al. Clin Cancer Res 2012;18: by American Association for Cancer Research

41 OXPHOS In Mitochondria OXPHOS- Oxida=ve Phosphoryla=on 41

42 Linking Oncogenes and Tumor Suppressor's to Tumor Cell Metabolism Cancer Cell Jun;13(6):

43 Cancer Cell Jun; 13(6):

44 Signalling and Transcriptional Machinery that Regulate Metabolism: PI3K/Akt Pathway Cantor J R, and Sabatini D M Cancer Discovery 2012;2: by American Association for Cancer Research 44

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46 p53 and Mitochondrial Respiration Science 2006;312:

47 p53 and Mitochondrial Respiration HCT116 Science 2006;312:

48 p53 and Mitochondrial Respiration Science 2006;312:

49 P53 Regulates Cellular Metabolism Shen L et al. Clin Cancer Res 2012;18: by American Association for Cancer Research 49

50 Summary: Factors Affecting Cancer Metabolism TW Mak et al., Nat Rev Cancer,

51 Glycolytic Inhibitors With Anticancer Activity Oncoene 2006; 25: , J Bioegnerg Biomembr 2007; 39:

52 Glycolytic Inhibitors With Anticancer Activity Oncogene (2006) 25, , J Bioenerg Biomembr Feb;44(1):

53 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:a by Cold Spring Harbor Laboratory Press 53

54 Application and Integration of Tools to Study Tumor Metabolism. Cantor J R, and Sabatini D M Cancer Discovery 2012;2: by American Association for Cancer Research 54

55 Summary 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 55

56 References Recommended Reading: 1. Tumor cell metabolism: cancer's Achilles' heel. Kroemer G, Pouyssegur J.Cancer Cell Jun;13(6): Understanding the Warburg effect: the metabolic requirements of cell proliferation. Vander Heiden MG, Cantley LC, Thompson CB. Science May 22;324(5930): On the origin of cancer cells. WARBURG O. Science Feb 24;123(3191): Required Reading: 1. Cancer cell metabolism: Warburg and beyond. Hsu PP, Sabatini DM.Cell Sep 5;134(5): p53 and metabolism. Vousden KH, Ryan KM. Nat Rev Cancer Oct; 9(10): p53 regulates mitochondrial respiration. Matoba S, Kang JG, Patino WD, Wragg A, Boehm M, Gavrilova O, Hurley PJ, Bunz F, Hwang PM. Science Jun 16;312(5780): Regulation of cancer cell metabolism. Cairns RA, Harris IS, Mak TW. Nat Rev Cancer Feb;11(2):