Regulation of ferroptotic cancer cell death by GPX4.

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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.

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Journal

Journal ID (iso-abbrev): Cell

Title: Cell

Publisher: Elsevier BV

ISSN (Electronic): 1097-4172

ISSN (Print): 0092-8674

Publication date (Electronic): Jan 16 2014

Volume: 156

Issue: 1-2

Affiliations

[1 ] Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12(th) Floor, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA.

[2 ] Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12(th) Floor, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA.

[3 ] Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12(th) Floor, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

[4 ] Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

[5 ] Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12(th) Floor, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA; Quantitative Proteomics Center, Columbia University, New York, NY 10027, USA.

[6 ] Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

[7 ] Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12(th) Floor, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA; Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12(th) Floor, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA; Howard Hughes Medical Institute, Columbia University, 1208 Northwest Corner Building, 12(th) Floor, 550 West 120(th) Street, MC 4846, New York, NY 10027, USA; Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA. Electronic address: bstockwell@columbia.edu.

Article

Publisher Item ID: S0092-8674(13)01544-4 Mid ID: NIHMS550564

DOI: 10.1016/j.cell.2013.12.010

PMC ID: 4076414

PubMed ID: 24439385

SO-VID: e480fb1c-9a60-4579-9207-86df09440e2a

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