Chemotherapy-induced pyroptosis is mediated by BAK/BAX-caspase-3-GSDME pathway and inhibited by 2-bromopalmitate

Many chemotherapy treatments induce Apoptosis or Pyroptosis through Bak/BAX-dependent mitochondrial pathway. Bak/Bax activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic Caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce Apoptosis or Pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNFα+CHX and navitoclax-induced Cancer cell Pyroptosis through a Bak/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the Pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapy-induced Pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapy-induced Pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the Pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced Pyroptosis and Apoptosis.