Regulation of ferroptotic cancer cell death by GPX4. Cell 2014 Jan 16;156(1-2):317-331
Date
01/21/2014Pubmed ID
24439385Pubmed Central ID
PMC4076414DOI
10.1016/j.cell.2013.12.010Scopus ID
2-s2.0-84892685001 (requires institutional sign-in at Scopus site) 5942 CitationsAbstract
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.
Author List
Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BRAuthor
Albert W. Girotti PhD Adjunct Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCarbolines
Carcinoma, Renal Cell
Cell Death
Cell Line, Tumor
Gene Knockdown Techniques
Glutathione
Glutathione Peroxidase
Heterografts
Humans
Lymphoma, B-Cell
Mice
Neoplasm Transplantation
Neoplasms
Piperazines
