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Updated: Oct 31 2018

Warburg Hypothesis

  • Overview
    • Principle idea
      • cancer cells generate energy via a unique mechanism
        • aerobic glycolysis
          • low energy generating pathway
          • cancer cells need high energy to facilitate their rapid division
          • hypoxia alone cannot explain this effect
          • generates high amounts of biosynthetic substrates for growth
          • unique protein expression profile
    • Metabolic changes
      • transport of glucose into cells
        • ↑↑ expression of GLUT1
          • allows for ↑↑ glucose uptake
        • ↑↑ expression of hexokinase 2
          • promotes glycolysis
          • inhibits apoptosis
          • ↑↑ affinity for ATP
          • ↓ inhibition by G6P
      • glycolysis
        • ↑↑ expression of fetal pyruvate kinase
          • favors the anaerobic pathway
        • ↑↑ shunting into pentose phosphate shunt
          • NADPH needed for biosynthesis
      • fatty acid metabolism
        • ↓↓ β-oxidation
          • ↑↑ lipid biosynthesis
      • amino acid metabolism
        • ↑↑ utilization of glutamine
          • replenish intermediates in the TCA cycle
            • e.g. oxaloacetate
      • cell growth
        • ↑↑ expression of Akt
          • controls proliferation of cells
          • regulates growth downstream of insulin
    • Clinical importance
      • cancer therapy
        • inhibitors of pyruvate kinase
          • forcing the cancer cell to use the TCA cycle
        • inhibitors of fetal pyruvate kinase
          • ↑ amount of adult pyruvate kinase
          • ↑ use of the TCA cycle
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