Therapeutic Implications of Targeting Energy Metabolism in Breast Cancer

Figure 3

Tumor cells have altered glucose metabolism. Many glycolytic enzymes are ubiquitously expressed in cancers. One such glycolytic enzyme is pyruvate kinase type M2 whose levels are found to be elevated in human cancer biopsies, compared to adjacent normal tissues. PKM2 is a key regulator of the metabolic budget system in tumor cells which promotes the Warburg effect and tumor growth. This tumor specific PKM2 can be switched between dimeric and tetrameric forms in cancer cells. Dimeric PKM2 has a higher 𝐾_𝑚 value for the substrate PEP than the tetrameric form of PKM2 and is inactive at physiological concentrations of PEP. PKM2 is allosterically activated by the glycolytic metabolite fructose-1,6-biphosphate (FBP) and serine. This leads to accumulation of energy rich phospho metabolites upstream of glycolytic pathway which are then channelled to macromolecule biosynthesis via pentose phosphate pathway (PPP). These pathways include pyrimidine, glycerol, and serine/glycine biosynthesis (red arrows) instead of leading to oxidative metabolism for energy production thereby promoting cancer cell proliferation and tumor growth.