Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers
Top Cited Papers
- 10 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 16 (12), 1351-1360
- https://doi.org/10.1038/s41589-020-0613-y
Abstract
Cancer cells rewire their metabolism and rely on endogenous antioxidants to mitigate lethal oxidative damage to lipids. However, the metabolic processes that modulate the response to lipid peroxidation are poorly defined. Using genetic screens, we compared metabolic genes essential for proliferation upon inhibition of cystine uptake or glutathione peroxidase-4 (GPX4). Interestingly, very few genes were commonly required under both conditions, suggesting that cystine limitation and GPX4 inhibition may impair proliferation via distinct mechanisms. Our screens also identify tetrahydrobiopterin (BH4) biosynthesis as an essential metabolic pathway upon GPX4 inhibition. Mechanistically, BH4 is a potent radical-trapping antioxidant that protects lipid membranes from autoxidation, alone and in synergy with vitamin E. Dihydrofolate reductase catalyzes the regeneration of BH4, and its inhibition by methotrexate synergizes with GPX4 inhibition. Altogether, our work identifies the mechanism by which BH4 acts as an endogenous antioxidant and provides a compendium of metabolic modifiers of lipid peroxidation.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (T32GM066699)
- Leukemia and Lymphoma Society
- Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada
- Canada Foundation for Innovation
- Foundation for the National Institutes of Health (DP2 CA228042-01)
- Pershing Square Foundation
- American Association of Collegiate Registrars and Admissions Officers
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