ASC/inflammasome-independent pyroptosis in ovarian cancer cells through translational augmentation of caspase-1

• DOI: 10.1016/j.isci.2023.108408
• Publication Date: 2023-11-07T08:05:39Z
• Authors: Ozlem Calbay; Ravi Padia; Mahmuda Akter; Lei Sun; Bin Li; Nicole Qian; Jianhui Guo; Zheng Fu; Lingtao Jin; Shuang Huang
• Keywords: Molecular biology; Science; Immunology; Q; Article; 3. Good health; Cancer

Canonical pyroptosis is type of programmed cell death depending on active caspase-1, and the inflammasome carries out caspase-1 activation. Here, we showed that docosahexaenoic acid (DHA) induced ovarian cancer cell deaths in caspase-1-dependent manner. DHA increased caspase-1 activity and led to interleukin-1β secretion and gasdermin D cleavage while disulfiram inhibited DHA-induced cell death, suggesting that DHA triggered pyroptosis. Intriguingly, ASC, the molecule recruiting caspase-1 to inflammasome for activation, was dispensable for DHA-induced pyroptosis. Instead, we observed remarkable elevation in caspase-1 abundance concurrent with the activation of caspase-1 in DHA-treated cells. As ectopically overexpressing caspase-1 resulted in robust amount of active caspase-1, we reason that DHA activates caspase-1 and pyroptosis through the generation of excessive amount of caspase-1 protein. Mechanistically, DHA increased caspase-1 by specifically accelerating caspase-1 protein synthesis via the p38MAPK/Mnk1 signaling pathway. We have uncovered an unknown pyroptosis mechanism in which caspase-1-dependent pyroptosis can occur without the participation of ASC/inflammasome.