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

Ozlem Calbay, Ravi Padia, Mahmuda Akter, Lei Sun, Bin Li, Nicole Qian, Jianhui Guo, Zheng Fu, Lingtao Jin, Shuang Huang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number108408
JournaliScience
Volume26
Issue number12
DOIs
StatePublished - Dec 15 2023

Keywords

  • Cancer
  • Immunology
  • Molecular biology

ASJC Scopus subject areas

  • General

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