Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis
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 molecu...
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doaj-be6d04f15e4d4ceb80b19d450fc9e9492021-05-04T23:08:54ZengeLife Sciences Publications LtdeLife2050-084X2014-05-01310.7554/eLife.02523Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosisScott J Dixon0Darpan N Patel1Matthew Welsch2Rachid Skouta3Eric D Lee4Miki Hayano5Ajit G Thomas6Caroline E Gleason7Nicholas P Tatonetti8Barbara S Slusher9Brent R Stockwell10https://orcid.org/0000-0002-3532-3868Department of Biological Sciences, Columbia University, New York, United StatesDepartment of Biological Sciences, Columbia University, New York, United StatesDepartment of Biological Sciences, Columbia University, New York, United StatesDepartment of Biological Sciences, Columbia University, New York, United StatesDepartment of Biological Sciences, Columbia University, New York, United StatesDepartment of Biological Sciences, Columbia University, New York, United StatesBrain Science Institute, Johns Hopkins Medicine, Baltimore, United StatesDepartment of Biological Sciences, Columbia University, New York, United StatesDepartment 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 StatesBrain Science Institute, Johns Hopkins Medicine, Baltimore, United States; Department of Neurology, Johns Hopkins Medicine, Baltimore, United StatesDepartment 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 StatesExchange 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.https://elifesciences.org/articles/02523reactive oxygen speciescell deathSLC7A11cystinesorafeniberastin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis eLife reactive oxygen species cell death SLC7A11 cystine sorafenib erastin |
author_facet |
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 |
author_sort |
Scott J Dixon |
title |
Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis |
title_short |
Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis |
title_full |
Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis |
title_fullStr |
Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis |
title_full_unstemmed |
Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis |
title_sort |
pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2014-05-01 |
description |
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. |
topic |
reactive oxygen species cell death SLC7A11 cystine sorafenib erastin |
url |
https://elifesciences.org/articles/02523 |
work_keys_str_mv |
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