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