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

By Scott J. Dixon, Darpan N. Patel, Matthew E. Welsch, R. Skouta, Eric D. Lee, M. Hayano, A. Thomas, Caroline E. Gleason, Nicholas P. Tatonetti, B. Slusher and 1 more. eLife, 2014

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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

Subfields: Molecular Biology, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/2758e740a934fe25ef36c87a28ff106b0e40c245

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Citations in the corpus

Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. (2022, positive): “GSH-dependent peroxidase to counter the oxidation of lipids in membranes (Ursini et al., 1982; Figure 2).”
From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, neutral): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
Targeting Metabolism for Cancer Therapy (2017, background): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript deplete intracellular glutathione in cancer cells, resulting in iron-dependent accumulation of ROS and a form of cell death termed ferroptosis (Dixon et al., 2012; Dixon et al., 2014; Yang et al., 2014).”
Metallothionein-1G Facilitates Sorafenib Resistance through Inhibition of Ferroptosis (2016, background): “, Ras, Raf, and PIK3CA)((40)) and kinase inhibition.((41)) Several genes or proteins responsible for the regulation of iron metabolism and lipid peroxidation have been involved in ferroptosis.”
FINO2 Initiates Ferroptosis Through GPX4 Inactivation and Iron Oxidation (2018, positive): “18 To test whether FINO 2 induces transcriptional changes similar to other ferroptosis inducers, we performed RT-qPCR to quantify the amount of CHAC1 mRNA in cells treated with erastin or FINO 2 (Figure 2C).”
Ferroptosis: process and function (2016, background): “1,7 Sorafenib.”