Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers
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...
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| Veröffentlicht in: | Nature chemical biology 2020-12, Vol.16 (12), p.1351-1360 |
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| creator | Soula, Mariluz Weber, Ross A. Zilka, Omkar Alwaseem, Hanan La, Konnor Yen, Frederick Molina, Henrik Garcia-Bermudez, Javier Pratt, Derek A. Birsoy, Kıvanç |
| description | 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.
Genetic screens reveal a compendium of metabolic modifiers of lipid peroxidation. Tetrahydrobiopterin is essential under GPX4 inhibition, acting as a radical-trapping antioxidant that inhibits lipid peroxidation and is regenerated by DHFR. |
| doi_str_mv | 10.1038/s41589-020-0613-y |
| format | Article |
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Genetic screens reveal a compendium of metabolic modifiers of lipid peroxidation. 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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.
Genetic screens reveal a compendium of metabolic modifiers of lipid peroxidation. Tetrahydrobiopterin is essential under GPX4 inhibition, acting as a radical-trapping antioxidant that inhibits lipid peroxidation and is regenerated by DHFR.</description><subject>631/67</subject><subject>631/80/82</subject><subject>631/92/287/1192</subject><subject>631/92/320</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antioxidants</subject><subject>Antioxidants - pharmacology</subject><subject>Autoxidation</subject><subject>Biochemical Engineering</subject><subject>Biochemistry</subject><subject>Bioorganic Chemistry</subject><subject>Biopterins - analogs & derivatives</subject><subject>Biopterins - pharmacology</subject><subject>Biosynthesis</subject><subject>Cancer</subject><subject>Carbolines - pharmacology</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemistry</subject><subject>Chemistry and Materials Science</subject><subject>Chemistry/Food 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determinants of cancer cell sensitivity to canonical ferroptosis inducers</title><author>Soula, Mariluz ; Weber, Ross A. ; Zilka, Omkar ; Alwaseem, Hanan ; La, Konnor ; Yen, Frederick ; Molina, Henrik ; Garcia-Bermudez, Javier ; Pratt, Derek A. ; Birsoy, Kıvanç</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c536t-38ffb24202a2f43a554676bebba015e0f8e22448b994d6600458565c57ddc5723</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>631/67</topic><topic>631/80/82</topic><topic>631/92/287/1192</topic><topic>631/92/320</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antioxidants</topic><topic>Antioxidants - pharmacology</topic><topic>Autoxidation</topic><topic>Biochemical Engineering</topic><topic>Biochemistry</topic><topic>Bioorganic Chemistry</topic><topic>Biopterins - analogs & derivatives</topic><topic>Biopterins - 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Biol</addtitle><date>2020-12-01</date><risdate>2020</risdate><volume>16</volume><issue>12</issue><spage>1351</spage><epage>1360</epage><pages>1351-1360</pages><issn>1552-4450</issn><eissn>1552-4469</eissn><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.
Genetic screens reveal a compendium of metabolic modifiers of lipid peroxidation. Tetrahydrobiopterin is essential under GPX4 inhibition, acting as a radical-trapping antioxidant that inhibits lipid peroxidation and is regenerated by DHFR.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>32778843</pmid><doi>10.1038/s41589-020-0613-y</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-4946-1436</orcidid><orcidid>https://orcid.org/0000-0002-7305-745X</orcidid><orcidid>https://orcid.org/0000-0003-3534-0470</orcidid><orcidid>https://orcid.org/0000-0001-7300-9370</orcidid><orcidid>https://orcid.org/0000-0002-7579-9895</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 631/67 631/80/82 631/92/287/1192 631/92/320 Antineoplastic Agents - pharmacology Antioxidants Antioxidants - pharmacology Autoxidation Biochemical Engineering Biochemistry Bioorganic Chemistry Biopterins - analogs & derivatives Biopterins - pharmacology Biosynthesis Cancer Carbolines - pharmacology Cell Biology Cell Line, Tumor Cell Proliferation - drug effects Chemistry Chemistry and Materials Science Chemistry/Food Science Cystine Cystine - antagonists & inhibitors Cystine - metabolism Dihydrofolate reductase Dose-Response Relationship, Drug Ferroptosis Ferroptosis - drug effects Ferroptosis - genetics Folic Acid Antagonists - pharmacology Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes Genetic screening Glutathione Glutathione peroxidase Humans Inhibition Jurkat Cells Lipid membranes Lipid metabolism Lipid peroxidation Lipid Peroxidation - drug effects Lipids Metabolic pathways Metabolism Methotrexate Methotrexate - pharmacology Oxidative Stress Peroxidase Peroxidation Phospholipid Hydroperoxide Glutathione Peroxidase - antagonists & inhibitors Phospholipid Hydroperoxide Glutathione Peroxidase - genetics Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism Piperazines - pharmacology Reactive Oxygen Species - metabolism Reductases Regeneration Signal Transduction Tetrahydrobiopterin Tetrahydrofolate Dehydrogenase - genetics Tetrahydrofolate Dehydrogenase - metabolism Trapping Vitamin E Vitamin E - pharmacology |
| title | Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T06%3A56%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Metabolic%20determinants%20of%20cancer%20cell%20sensitivity%20to%20canonical%20ferroptosis%20inducers&rft.jtitle=Nature%20chemical%20biology&rft.au=Soula,%20Mariluz&rft.date=2020-12-01&rft.volume=16&rft.issue=12&rft.spage=1351&rft.epage=1360&rft.pages=1351-1360&rft.issn=1552-4450&rft.eissn=1552-4469&rft_id=info:doi/10.1038/s41589-020-0613-y&rft_dat=%3Cproquest_pubme%3E2471569462%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2471569462&rft_id=info:pmid/32778843&rfr_iscdi=true |