α-KG Causes Pyroptosis In Cancer Cell Through Caspase-8

Cell death is a very complex and important biological process.It regulates various physiological functions and maintain homeostasis.The imbalance of cell death will lead to the occurrence of various diseases,including cancer,which is still a difficult problem.Therefore,further understanding of the mechanism of cell death and signal transduction pathway will help us to deal with various diseases.Pyroptosis is a kind of regulatory cell death mediated by Gasdermins.The cleavage of gasdermin by protease releases the N-terminal domain,which then forms the N-terminal oligomerization.The N-terminal domain,once translocated to the cell membrane,forms pores,thereby resulting in membrane permeability changes,cell swelling and membrane rupture.The function of pyroptosis has attracted more and more attention these years in cancer research.It has been reported that GSDME mediated cell death is related to the side effects of chemotherapy.So,specifical induction of pyroptosis in tumor cells and avoiding damage to normal cells and tissues become a key issue.Inducing pyroptosis specifically in tumor cells may be a good strategy in the treatment of tumor,because it can not only overcome the apoptosis resistance of tumor cells,but also trigger antitumor immunity.However,the specific inducers of pyroptosis are known less.Cell fate is closely related to metabolic homeostasis.α-ketoglutarate(α-KG)is an important metabolite in the tricarboxylic acid(TCA)cycle.It plays an important role in lipid synthesis,oxidative stress,protein modification,autophagy and cell death.Studies have shown that α-KG is a promising anti-tumor drug.However,the role of αKG in pyroptosis has not been reported.In this paper,we found that membrane permeable α-ketoglutarate,DM-αKG can cause pyroptosis in HeLa cells,and this kind of cell death is mediated by Caspase-8GSDMC pathway.This discovery for the first time links cell metabolism with cell death.We believe that the follow-up in-depth research will provide important theoretical support and research ideas for clinical tumor treatment through pyroptosis.