Format

Send to

Choose Destination
Elife. 2014 May 20;3:e02523. doi: 10.7554/eLife.02523.

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

Author information

1
Department of Biological Sciences, Columbia University, New York, United States.
2
Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States.
3
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.
4
Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States Department of Neurology, Johns Hopkins Medicine, Baltimore, United States.
5
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.

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 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.

KEYWORDS:

SLC7A11; cell death; cystine; erastin; reactive oxygen species; sorafenib

PMID:
24844246
PMCID:
PMC4054777
DOI:
10.7554/eLife.02523
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center