Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis.
Exchange of extracellular cystine for intracellular glutamate by the antiporter system xc (-) is implicated in numerous pathologies. Pharmacological agents that inhibit system xc (-) activity with high potency have long been sought, but have remained elusive. In this study, we report that the small molecule erastin is a potent, selective inhibitor of system xc (-). RNA sequencing revealed that inhibition of cystine-glutamate exchange leads to activation of an ER stress response and upregulation of CHAC1, providing a pharmacodynamic marker for system xc (-) inhibition. We also found that the clinically approved anti-cancer drug sorafenib, but not other kinase inhibitors, inhibits system xc (-) function and can trigger ER stress and ferroptosis. In an analysis of hospital records and adverse event reports, we found that patients treated with sorafenib exhibited unique metabolic and phenotypic alterations compared to patients treated with other kinase-inhibiting drugs. Finally, using a genetic approach, we identified new genes dramatically upregulated in cells resistant to ferroptosis.DOI: http://dx.doi.org/10.7554/eLife.02523.001.
Department of Biological Sciences, Columbia University, New York, United States.
Scott J
SJ
Dixon
Department of Biological Sciences, Columbia University, New York, United States.
Darpan N
DN
Patel
Department of Biological Sciences, Columbia University, New York, United States.
Matthew
M
Welsch
Department of Biological Sciences, Columbia University, New York, United States.
Rachid
R
Skouta
Department of Biological Sciences, Columbia University, New York, United States.
Eric D
ED
Lee
Department of Biological Sciences, Columbia University, New York, United States.
Miki
M
Hayano
Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States.
Ajit G
AG
Thomas
Department of Biological Sciences, Columbia University, New York, United States.
Caroline E
CE
Gleason
Department of Biomedical Informatics, Columbia University, New York, United States Department of Medicine, Columbia University, New York, United States Department of Systems Biology, Columbia University, New York, United States.
Nicholas P
NP
Tatonetti
Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States Department of Neurology, Johns Hopkins Medicine, Baltimore, United States.
Barbara S
BS
Slusher
Department of Biological Sciences, Columbia University, New York, United States Department of Systems Biology, Columbia University, New York, United States Department of Chemistry, Columbia University, New York, United States Howard Hughes Medical Institute, Columbia University, New York, United States bstockwell@columbia.edu.
Brent R
http://orcid.org/0000-0002-3532-3868
BR
Stockwell
D015089:20-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D003553:Cystine / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000494:pharmacology; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017423:Sequence Analysis, RNA; D000077157:Sorafenib; D013329:Structure-Activity Relationship; D059467:Transcriptome / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D027182:Amino Acid Transport System y+; D015415:Biomarkers; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; C477224:erastin; D009536:Niacinamide; D018698:Glutamic Acid; D003553:Cystine; D000077157:Sorafenib; D007501:Iron; D015089:20-Hydroxysteroid Dehydrogenases
SLC7A11; cell death; cystine; erastin; reactive oxygen species; sorafenib