Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis

Scott J. Dixon, Darpan Patel, Matthew Welsch, Rachid Skouta, Eric Lee, Miki Hayano, Ajit G. Thomas, Caroline Gleason, Nicholas Tatonetti, Barbara S. Slusher, Brent R. Stockwell

Research output: Contribution to journalArticlepeer-review

Abstract

Exchange of extracellular cystine for intracellular glutamate by the antiporter system Xc- is implicated in numerous pathologies. Pharmacological agents that inhibit system Xc- activity have long been sought, but have remained elusive. Here, 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.

Original languageEnglish (US)
Article numbere02523
JournaleLife
Volume2014
Issue number3
DOIs
StatePublished - May 20 2014

Keywords

  • Cystine
  • Erastin
  • Reactive oxygen species
  • SLC7A11
  • Sorafenib

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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