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Regulation of ferroptotic cancer cell death by GPX4.
Yang, Wan Seok; SriRamaratnam, Rohitha; Welsch, Matthew E; Shimada, Kenichi; Skouta, Rachid; Viswanathan, Vasanthi S; Cheah, Jaime H; Clemons, Paul A; Shamji, Alykhan F; Clish, Clary B; Brown, Lewis M; Girotti, Albert W; Cornish, Virginia W; Schreiber, Stuart L; Stockwell, Brent R.
Afiliação
  • Yang WS; Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
  • SriRamaratnam R; Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
  • Welsch ME; Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
  • Shimada K; Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
  • Skouta R; Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
  • Viswanathan VS; Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
  • Cheah JH; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Clemons PA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Shamji AF; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Clish CB; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Brown LM; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
  • Girotti AW; Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
  • Cornish VW; Quantitative Proteomics Center, Columbia University, New York, NY 10027, USA.
  • Schreiber SL; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • Stockwell BR; Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
Cell ; 156(1-2): 317-331, 2014 Jan 16.
Article em En | MEDLINE | ID: mdl-24439385
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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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piperazinas / Carbolinas / Morte Celular / Glutationa Peroxidase Idioma: En Ano de publicação: 2014 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piperazinas / Carbolinas / Morte Celular / Glutationa Peroxidase Idioma: En Ano de publicação: 2014 Tipo de documento: Article