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

  1. Scott J Dixon
  2. Darpan N Patel
  3. Matthew Welsch
  4. Rachid Skouta
  5. Eric D Lee
  6. Miki Hayano
  7. Ajit G Thomas
  8. Caroline E Gleason
  9. Nicholas Tatonetti
  10. Barbara S Slusher
  11. Brent R Stockwell  Is a corresponding author
  1. Columbia University, United States
  2. Johns Hopkins Medicine Brain Science Institute, United States
Research Article
  • Cited 261
  • Views 9,766
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Cite this article as: eLife 2014;3:e02523 doi: 10.7554/eLife.02523

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.

Article and author information

Author details

  1. Scott J Dixon

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Darpan N Patel

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Matthew Welsch

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Rachid Skouta

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Eric D Lee

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Miki Hayano

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ajit G Thomas

    Johns Hopkins Medicine Brain Science Institute, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Caroline E Gleason

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nicholas Tatonetti

    Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Barbara S Slusher

    Johns Hopkins Medicine Brain Science Institute, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. 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.

Reviewing Editor

  1. Wilfred van der Donk, University of Illinois-Urbana Champaign, United States

Publication history

  1. Received: February 12, 2014
  2. Accepted: May 17, 2014
  3. Accepted Manuscript published: May 20, 2014 (version 1)
  4. Version of Record published: June 17, 2014 (version 2)

Copyright

© 2014, Dixon et al.

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.

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