Regulation of Ferroptotic Cancer Cell Death by GPX4

被引：5583

作者：

Yang, Wan Seok ^{[1
]}

SriRamaratnam, Rohitha ^{[2
]}

Welsch, Matthew E. ^{[2
]}

Shimada, Kenichi ^{[1
]}

Skouta, Rachid ^{[1
]}

Viswanathan, Vasanthi S. ^{[1
,4
]}

Cheah, Jaime H. ^{[4
]}

Clemons, Paul A. ^{[4
]}

Shamji, Alykhan F. ^{[4
]}

Clish, Clary B. ^{[4
]}

Brown, Lewis M. ^{[1
,6
]}

Girotti, Albert W. ^{[5
]}

Cornish, Virginia W. ^{[2
]}

Schreiber, Stuart L. ^{[4
]}

Stockwell, Brent R. ^{[1
,2
,3
,7
]}

机构：

[1] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

[2] Columbia Univ, Dept Chem, New York, NY 10027 USA

[3] Columbia Univ, Howard Hughes Med Inst, New York, NY 10027 USA

[4] Broad Inst Harvard & MIT, Cambridge, MA 02142 USA

[5] Med Coll Wisconsin, Dept Biochem, Milwaukee, WI 53226 USA

[6] Columbia Univ, Quantitat Prote Ctr, New York, NY 10027 USA

[7] Columbia Univ, Dept Syst Biol, Med Ctr, New York, NY 10032 USA

来源：

CELL | 2014年 / 156卷 / 1-2期

基金：

美国国家卫生研究院;

关键词：

GLUTATHIONE-PEROXIDASE; 4; HUMAN TUMOR-CELLS; OXIDATIVE STRESS; RAS; IDENTIFICATION; GLUTATHIONE-PEROXIDASE-4; EXPRESSION; MECHANISM; APOPTOSIS; GROWTH;

D O I：

10.1016/j.cell.2013.12.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosisinducing 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.

引用

页码：317 / 331

页数：15

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