Pkm2 is a target of huhs1015 for inducing colonic cancer cell death

The newly synthesized naftopidil analog HUHS1015 has been developed as an anticancer drug. The present study aimed at understanding the mechanism underlying HUHS1015-induced cell death in CW2 and Caco-2 human colonic cancer cells. HUHS1015 reduced cell viability in CW2 and Caco-2 cells in a concentration (10-100 μM)-dependent manner. HUHS1015 decreased pyruvate kinase M2 (PKM2) protein, and the effect was inhibited by the autophagy inhibitor 3-methyladenine. PKM2 deficiency activated caspase-3, -4, -8, and -9 in Caco-2 cells, although such effect was not obtained with CW2 cells. Moreover, PKM2 deficiency induced early apoptosis and late apoptosis/secondary necrosis in CW2 cells and primary necrosis, early apoptosis, and late apoptosis/secondary necrosis in Caco-2 cells. The results of the present study show that HUHS1015 decreases PKM2 protein due to autophagic degradation, to initiate cell death such as necrosis and caspase-dependent and -independent apoptosis in CW2 and Coco-2 cells.