Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin

Chemotherapy drugs can cause pyroptotic cell death by activating caspase-3 to cleave gasdermin E, potentially contributing to their toxicity and adverse effects. The negative side effects of chemotherapy are well documented but the mechanisms behind them are not always known. Feng Shao and colleagues show that chemotherapy drug treatment of gasdermin-E-expressing tumour cells results in a caspase-3-dependent switch from apoptotic to pyroptotic cell death. The majority of human tumours tested appeared to have lost expression of gasdermin E, whereas normal tissues express it. This observation has potential implications for the treatment of gasdermin-E-expressing tumours, and for chemotherapy-induced tissue damage. Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide1,2,3. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity4,5,6,7,8,9. GSDMD belongs to a gasdermin family that shares the pore-forming domain4,6,10. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5)11, can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme−/− (also known as Dfna5−/−) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.