Regulation of Ferroptotic Cancer Cell Death by GPX4

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2014 Jan 21

PMID 24439385

Citations 2882

Authors

Wan Seok Yang

Rohitha Sriramaratnam

Matthew E Welsch

Kenichi Shimada

Rachid Skouta

Vasanthi S Viswanathan

Jaime H Cheah

Paul A Clemons

Alykhan F Shamji

Clary B Clish

Lewis M Brown

Albert W Girotti

Virginia W Cornish

Stuart L Schreiber

Brent R Stockwell

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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