Warburg effect & cancer
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WARBURG EFFECT: Hallmark of CANCER. What, Why & How?
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Warburg effect & cancer
- 1. Warburg effect in Cancer The major metabolic shift Reprogramming Energy Metabolism
- 2. Learning Outcomes • Introduction • The Warburg effect • Why and how of this effect • What is the significance
- 3. ENERGY for Cells Mitochondria Oxygen dependent Process Oxidative phosphorylation ALSO Glycolysis Does not require oxygen Cytoplasm 36 ATP 2 ATP More efficient
- 4. Adequate oxygen ATP is generated by Oxidative Phosphoryation As Oxygen Decreases Shift from Oxidative phosphorylation to Glycolysis PASTEUR EFFECT Anaerobic glycolysis
- 5. Otto Heinrich Warburg Early 20th Century German Physiologist Observed that cancer cells had increased rates of glycolysis Despite the availability of adequate oxygen levels Aerobic glycolysis WARBURG EFFECT
- 9. The puzzling questions Why do cancer cells activate glycolysis despite the presence of oxygen? How do they manage to activate glycolysis despite the presence of oxygen? Is this phenomenon Cancer specific?
- 10. Is this phenomenon Cancer specific?
- 11. No! This is evident in rapidly growing normal tissues too as in embryonic tissue It is a property of growing cells but got “stuck” in cancer cells!!
- 12. Why do cancer cells activate glycolysis despite the presence of oxygen? Assures ATP synthesis when tumor outgrows its oxygen supply The metabolic intermediates of AEROBIC GLYCOLYSIS provides raw material for the synthesis of cellular components in these rapidly dividing tumor cells! And also favor tumor growth Release of acid lowers extracellular pH which favors tumor invasion and suppresses immune effectors
- 13. How do they manage to activate glycolysis despite the presence of oxygen?
- 14. Overexpression of Hypoxia inducible factor 1 ( HIF 1) Increases transcription of many genes Codes proteins favoring cancer Glucose metabolism Apoptosis resistance Angiogenesis
- 15. • HIF-1 increases glucose uptake by upregulating GLUT1 expression. • HIF-1 increases glucose phosphorylation by upregulating hexokinase 2 expression • Increase in HIF-1 has similar effect as loss of p53 function( results in greater glycolytic flux, reduced pyruvate oxidation, and reduced production of ATP by oxidative phosphorylation) Glucose
- 16. How do they manage to activate glycolysis despite the presence of oxygen? • Induction of glycolytic enzymes BY overexpression of HIF 1 • Induction of Pyruvate dehydrogenase kinase • Down regulation of mitochondrial enzymes and decrease in the number of mitochondria • Mitochondrial defects due to mutations in mitochondrial DNA leading to malfunction of oxidative phosphorylation
- 17. Significance of understanding Warburg effect So what??
- 18. Diagnostic Therapeutic This property of “glucose hunger” is used in PET scanning of solid tumors 18F-flourodeoxyglucose, a nonmetabolizable glucose derivative of glucose is used where this is preferentially taken by tumor cells/rapidly dividing cells Numerous Glycolytic inhibitors have been developed which can be potential anticancer drugs
- 19. Viewpoint! • Warburg effect is a growth promoting metabolic alteration in cancer cells • One of the Hallmarks of Cancer! • lots of explanations are given for this effect. • However the exact cause and its value,.. As of now still remains elusive!
- 20. Summary • Introduction • The Warburg effect • Why and how of this effect • What is the significance