Chemotherapy Drugs Induce Pyroptosis Through Caspase-3 Cleavage Of GSDME

Pyroptosis is a very recently defined Programmed cell-death(PCD).Different from apoptosis,pyroptosis can lead to the disruption of cell membrane,cell swelling and inflammation eventually.The activation of pyroptosis is induced by inflammatory caspases,including caspase-1/4/5/11.Caspase-1 is ignited by the assembling of inflammasome,which is a multi-protein platform responding for the invaded microbes.Caspase-4/5/11 can recognize the cytosolic lipopolysaccharide/LPS from Gram-negative bacteria directly.In addition,this recognition results the oligomerization and activation of caspase-4/5/11.Feng Shao's lab and Vishva Dixit's lab have defined that gasdermin-D(GSDMD)is the executioner of pyroptosis in 2015.Activated caspase-1/4/5/11 cleave the hinge region of GSDMD,which releases the pore-forming activity of its gasdermin-N domain.As a result these caspases are classified as inflammatory caspases to distinguish them from classical apoptotic caspases including caspase-3.Here,we found GSDME has a conserved tetrapeptide,which is suitable for the cleavage by caspase-3.Activated caspase-3 can cleave GSDME efficiently and generating a GSDME-N fragment perforates cell membranes and thereby causes pyroptosis.Chemotherapy drugs and TNF induce apoptosis through intrinsic and extrinsic apoptotic pathway,respectively,which has been reported by lots of papers.Activated caspase-3 has long been accepted as the marker of apoptosis.Now we proved that GSDME can switch caspase-3-mediated apoptosis induced by these triggers to pyroptosis.GSDME is epigenetically silenced in tumorigenesis but highly expressed in normal tissue.Chemotherapy drugs cause tissue damage as anti-cancer therapy is applied.Since caspase-3 could be activated in response to DNA damage induced by chemotherapy drugs,we showed that such tissue damage is mediated by pyroptosis activated by caspase-3 cleavage of GSDME.Genetic ablation of GSDME in mice models can largely reduce chemotoxicity induced by these drugs.These findings changed the dogma on caspase-3 of its induction of apoptosis,and suggested the molecular mechanism of chemotherapy caused toxicity and provided new strategy on improving chemotherapy efficiency for the first time.