Aerobic Glycolysis & Cancer

1. Aerobic Glycolysis & Cancer Gemma Leung, Imninder Gill, David Liu, Cheryl Wong PHM142 Fall 2012 Instructor: Dr. Jeffrey Henderson

2. Glycolysis

3. Oxidative phosphorylation

4. ATP Yield

5. What is the Warburg Effect? • 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.

6. Question: Why do cancer cells exhibit the Warburg effect? • Hypotheses: • Hypoxic conditions • Alternate uses for substrates and enzymes for the TCA • Observation: Other cells undergoing rapid cellular expansion also undergo aerobic glycolysis.

7. Question: How is the Warburg effect established in cancer cells?

8. Possible mechanisms: • Transcriptional regulation of the Warburg effect • Metabolic isoform switching • Post-translational regulation • Micro-RNA regulation • Genomic regulation • ATP consumption in futile cycles • Mitochondrial dysfunction

9. Possible mechanisms: • Transcriptional regulation of the Warburg effect • Hypoxia Inducible Factor (HIF) • C-Myc oncogene • P53 tumour suppressor gene

10. HIF & Glycolysis

11. HIF & Glycolysis

12. Myc-oncogene & Glycolysis

13. P53 & Glycolysis

14. Cancer Detection With Pyruvate kinase

15. Cancer Detection With Positron Electron Tomography (PET)

16. Targeting Glycolysis Disrupting glycolysis in cancer cells via • Inhibiting glucose uptake • Inhibiting glycolysis-related enzymes

19. Summary • 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. • Changes in the 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 hypoxia inducible factor, c-Myc and p53. • PKM2 can function as a transcriptional cofactor of HIF1. Hydroxylation of PKM2 with prolyl hydroxylase 3 can enhance its binding to HIF1 • Binding of PKM2 to HIF1 aids HIF1 binding and helps bring in p300 to hypoxia gene response elements, increasing gene expression rate • Cancer cells have been found to have embryonic PKM2 and no PKM1. Through suppression of PKM2 and addition of PKM1, tumour growth can be slowed or stopped. • Using glucose analog FDG, PET can pinpoint the location of cancer cells • Drugs currently in development/clinical trials to disrupt aerobic glycolysis in cancer cells, are focused on blocking glucose uptake, or inhibiting specific glycolytic enzymes. • Problems with unwanted toxicity towards non-cancerous cells, and specificity to cancerous cells.

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