Updated: 10/31/2018

Warburg Hypothesis

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Overview
  • The Warburg hypothesis states that neoplastic cells undergo unique changes in metabolism, favoring anaerobic glycolysis.  This occurs in a hypoxic and acidotic microenvironment. 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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