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Cancer Cell Metabolism
Nadi Wickramasekera. Ph.D.
Dept. of Pharmacology and Therapeutics (L4-107)
1
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
3
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)
4
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)
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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 8
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 Pyruvicacid
11
Pyruvate
Glucose
CYTOSOL
No O2 presentFermentation
Ethanolor
lactate
Acetyl CoA
MITOCHONDRION
O2 present Cellular respiration
Citricacidcycle
Anaerobic Respira=on
Aerobic Respira=on
Fate of Pyruvate
13
Overall ATP Production
Electron Transport System 34Citric Acid Cycle 2Glycolysis 2SUBTOTAL 38NADH Transport into Mitochondrion* -2TOTAL 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 mole18
Net ATP Yield
34 to 36 molecules ATP for every glucose molecule
about 40% efficiency
ATP
19
The high-energy ATP molecules store 7.3 kcal of energy per mole
The Warburg Theory of Cancer or "Warburg hypothesis"
Dr. O4o 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
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.
What is the Warburg Effect?
23
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
Warburg Effect
QO2: oxygen consumed/ml
QMO2: lacHc acid produced aerobically /ml
QMN2: lacHc acid produced anaerobically /ml
Science 1956;124: (3215) 269-‐70
The higher the malignancy, the greater the fermentaHon and the smaller the respiraHon
26
Nature Rev Cancer 2004;4:891-‐9Low malignancy High Malignancy
Higher Glucose Uptake Correlates With More Aggressive Phenotypes and Poorer Clinical Outcomes
27
Cancer: Principles & Prac/ce of Oncology 9th Edi8on
Clinical FDG-PET Scanning Exploits Cancer Metabolism
MaBhew 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
28
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 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
Cell Proliferation Requires the Conversion of Nutrients into Biomass
Non-proliferating Cells
NUTRIENTS NU
TRI
ES
TATP
Proliferating Cancer Cells
NU
TRI
ES
T
NUTRIENTS
NUTRIENTS
33
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
MaBhew G. Vander Heiden. Nat Rev Drug Discov. 2011 35
10%
Normal differentiated cellsOxidative Phosphorylation
CO2
Proliferating cells Aerobic Glycolysis
Pyruvate Kinase (PK-M2 ) Activity is Regulated by cell Growth Signals and Promotes Anabolic Metabolism
36
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
38
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
39
HIF-1 Pathway
Meijer T W et al. Clin Cancer Res 2012;18:5585-5594
©2012 by American Association for Cancer Research40
Linking Oncogenes and Tumor Suppressor's to Tumor Cell Metabolism
42Cancer 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
Shen L et al. Clin Cancer Res 2012;18:1561-1567©2012 by American Association for Cancer Research
49
P53 Regulates Cellular Metabolism
51
Glycolytic Inhibitors With Anticancer Activity
Oncoene 2006; 25:4633-46 , J Bioegnerg Biomembr 2007; 39:267-74
52Oncogene (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 Press53
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
54
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
55
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.
56
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