Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis
Scott J Dixon,
Darpan N Patel,
Matthew Welsch,
Rachid Skouta,
Eric D Lee,
Miki Hayano,
Ajit G Thomas,
Caroline E Gleason,
Nicholas P Tatonetti,
Barbara S Slusher,
Brent R Stockwell
Affiliations
Scott J Dixon
Department of Biological Sciences, Columbia University, New York, United States
Darpan N Patel
Department of Biological Sciences, Columbia University, New York, United States
Matthew Welsch
Department of Biological Sciences, Columbia University, New York, United States
Rachid Skouta
Department of Biological Sciences, Columbia University, New York, United States
Eric D Lee
Department of Biological Sciences, Columbia University, New York, United States
Miki Hayano
Department of Biological Sciences, Columbia University, New York, United States
Ajit G Thomas
Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States
Caroline E Gleason
Department of Biological Sciences, Columbia University, New York, United States
Nicholas P Tatonetti
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
Barbara S Slusher
Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins Medicine, Baltimore, United States
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
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.