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
Affiliations
Ozlem Calbay
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA
Ravi Padia
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA
Mahmuda Akter
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA
Lei Sun
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA
Bin Li
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA
Nicole Qian
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA
Jianhui Guo
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA
Zheng Fu
Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA
Lingtao Jin
Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA
Shuang Huang
Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL 32610, USA; Corresponding author
Summary: 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.
