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

  • Cell Death Dis. 2020 Apr 24;11(4):281. doi: 10.1038/s41419-020-2476-2.
Lei Hu   #  1  2  3 ,  Meng Chen   #  1  2  3 ,  Xueran Chen  1  3 ,  Chenggang Zhao  1  2  3 ,  Zhiyou Fang  1  3 ,  Hongzhi Wang  1  3 ,  Haiming Dai  4  5
Affiliations
  • 1. Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, 230031, Hefei, China.
  • 2. University of Science and Technology of China, 230026, Hefei, China.
  • 3. Hefei Cancer Hospital, Chinese Academy of Sciences, 230031, Hefei, China.
  • 4. Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, 230031, Hefei, China. [email protected].
  • 5. Hefei Cancer Hospital, Chinese Academy of Sciences, 230031, Hefei, China. [email protected].
  • # Contributed equally.
PMID: 32332857 DOI: 10.1038/s41419-020-2476-2
Abstract

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.

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