Attacking Metabolism-Related Enzymes in Cancer: Multi-Mode Investigation of PKM2-Inhibition and Autophagy

There is metabolic re-programming of cancer cells in order to sustain rapid proliferation. One of the most important glycolytic enzymes is pyruvate kinase M2 (PKM2) which is commonly overexpressed in cancers and is central to the Warburg effect. This research paper examines whether a novel small-molecule inhibitor, Cpd-12, can be effectively used to treat PKM2 and downstream signaling through this enzyme on the metabolism and autophagy of cancer cells. We provide and show that Cpd-12 is effective in inhibiting the PKM2 activity using combination of in silico molecular docking, in vitro enzyme kinetics and cell based assays on HeLa (cervical cancer) and MCF-7 (breast cancer) cell lines (IC₅₀ = 1.8 ± 0.3 µM). The inhibition resulted in high concentrations of upstream glycolytic intermediates, lactate reduction, and ATP reduction. Moreover, Cpd-12 treatment caused cytostatic response, colony formation, and autophagy indicated by the heightened LC3-II conversion and p62 degradation. These results make PKM2 a strong therapeutic target and conclude that its inhibition can disrupt the metabolic flow in cancer and cause protective autophagy, which can be used in combination therapies.