Regulation of Ferroptotic Cancer Cell Death by GPX4
Menée à l'aide de xénogreffes et sur 177 lignées cellulaires cancéreuses, cette étude met en évidence le rôle joué par la protéine GPX4 dans un mécanisme de mort cellulaire non apoptotique appelé ferroptose
Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. "Metabolomic profiling revealed GSH depletion as one mechanism of ferroptosis "Chemoproteomics identified GPX4 as a target for RSL3, a second ferroptosis inducer "GPX4 is a central regulator of ferroptosis, akin to bcl-2 in apoptosis "DLBCLs and renal cell carcinomas are sensitive to ferroptotic cell death A chemoproteomic screen identifies a glutathione peroxidase as an essential regulator of a nonapoptotic form of cell death known as ferroptosis.