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

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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.

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Scott J Dixon

Columbia University, New York, United States

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The authors declare that no competing interests exist.
Darpan N Patel

Columbia University, New York, United States

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The authors declare that no competing interests exist.
Matthew Welsch

Columbia University, New York, United States

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The authors declare that no competing interests exist.
Rachid Skouta

Columbia University, New York, United States

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The authors declare that no competing interests exist.
Eric D Lee

Columbia University, New York, United States

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The authors declare that no competing interests exist.
Miki Hayano

Columbia University, New York, United States

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The authors declare that no competing interests exist.
Ajit G Thomas

Johns Hopkins Medicine Brain Science Institute, Baltimore, United States

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The authors declare that no competing interests exist.
Caroline E Gleason

Columbia University, New York, United States

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The authors declare that no competing interests exist.
Nicholas Tatonetti

Columbia University, New York, United States

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The authors declare that no competing interests exist.
Barbara S Slusher

Johns Hopkins Medicine Brain Science Institute, Baltimore, United States

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The authors declare that no competing interests exist.
Brent R Stockwell

Columbia University, New York, United States

For correspondence
bstockwell@columbia.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Human subjects: The data analysis described in this manuscript was covered under the Columbia Institutional Review Board (IRB) protocol number AAAL0601 and performed according to NIH and Columbia University guidelines.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.