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Cell DOI:10.1016/j.cell.2013.12.010

Regulation of ferroptotic cancer cell death by GPX4.

Publication TypeJournal Article
Year of Publication2014
AuthorsYang, WSeok, 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, BR
JournalCell
Volume156
Issue1-2
Pages317-31
Date Published2014 Jan 16
ISSN1097-4172
KeywordsAnimals, Carbolines, Carcinoma, Renal Cell, Cell Death, Cell Line, Tumor, Gene Knockdown Techniques, Glutathione, Glutathione Peroxidase, Heterografts, Humans, Lymphoma, B-Cell, Mice, Neoplasm Transplantation, Neoplasms, Piperazines
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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S0092-8674(13)01544-4
DOI10.1016/j.cell.2013.12.010
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24439385?dopt=Abstract

Alternate JournalCell
PubMed ID24439385
PubMed Central IDPMC4076414
Grant ListRC2 CA148399 / CA / NCI NIH HHS / United States
1S10RR025431-01A1 / RR / NCRR NIH HHS / United States
5R01-CA70823-15 / CA / NCI NIH HHS / United States
S10 RR025431 / RR / NCRR NIH HHS / United States
5R01CA097061 / CA / NCI NIH HHS / United States
R01 CA161061 / CA / NCI NIH HHS / United States
/ / Intramural NIH HHS / United States
R01 GM085081 / GM / NIGMS NIH HHS / United States
RC2-CA148399 / CA / NCI NIH HHS / United States
R01 CA097061 / CA / NCI NIH HHS / United States
R01 CA070823 / CA / NCI NIH HHS / United States
5R01GM085081 / GM / NIGMS NIH HHS / United States
R01CA161061 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
R21 CA177591 / CA / NCI NIH HHS / United States