Regulation of ferroptotic cancer cell death by GPX4.
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.
Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
Wan Seok
WS
Yang
Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
Rohitha
R
SriRamaratnam
Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
Matthew E
ME
Welsch
Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
Kenichi
K
Shimada
Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
Rachid
R
Skouta
Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Vasanthi S
VS
Viswanathan
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Jaime H
JH
Cheah
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Paul A
PA
Clemons
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Alykhan F
AF
Shamji
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Clary B
CB
Clish
Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.|Quantitative Proteomics Center, Columbia University, New York, NY 10027, USA.
Lewis M
LM
Brown
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Albert W
AW
Girotti
Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.
Virginia W
VW
Cornish
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Stuart L
SL
Schreiber
Department of Biological Sciences, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.|Department of Chemistry, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.|Howard Hughes Medical Institute, Columbia University, 1208 Northwest Corner Building, 12 Floor, 550 West 120 Street, MC 4846, New York, NY 10027, USA.|Department of Systems Biology, Columbia University Medical Center, New York, NY 10032, USA.
Brent R
BR
Stockwell
D000818:Animals; D002243:Carbolines / Q000494:pharmacology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D010879:Piperazines / Q000494:pharmacology*
D002243:Carbolines; D010879:Piperazines; C587550:RSL3 compound; C477224:erastin; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; D005978:Glutathione