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Title:
A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers | Nature Communications
Description:
Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers. KEAP1 mutations are frequently observed in NSCLC and lead to drug resistance. Here, the authors show that KEAP1 mutations in lung cancer cells leads to FSP1 upregulation through NRF2, resulting in ferroptosis resistance and radioresistance.
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Keywords {π}
keap, cells, ferroptosis, cancer, fsp, pubmed, cell, fig, article, lung, google, scholar, cas, data, nrf, supplementary, central, lipid, tumor, levels, gpx, expression, peroxidation, mutant, nature, coq, cba, cancers, deficient, rsl, treatment, death, tumors, study, deletion, target, xray, slca, fin, resistance, survival, deficiency, irradiation, analysis, protein, fins, radiation, class, source, pathway,
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nature portfolio privacy policy middle line represents advertising apoptosis inhibitor z-vad-fmk fsp1 promoter-luciferase activities p62-keap1-nrf2 pathway protects depmap data portal reprints foxo-bnip3 axis exerts perform real-time pcr cancer genome atlas japan hek-293t cells treated cancer research communities cystine transporter slc7a11/xct keap1 deficiency-induced resistance n-terminal v5 tag thermofisher scientific esmo open 5 kopchick research award rt-induced lipid peroxidation slc7a11-keap1 dko cells rt-induced cell death21 cell culture media lentivirus vector plx304-blasticidin necroptosis inhibitor necrostatin-1s gpx4-keap1 dko cells org/portal/ p53-inducible gene downregulated bi-dimensional tumor measurements remove serum-derived coq institutional research fund 100βmm tris-hcl ph8 cold dmem media 100βΞΌm tert-butyl-hydroquinone molina dasΒ &Β boyi gan tsc-mtor signaling pathways lncrna nbr2 engages glutathione-independent ferroptosis suppressor patient-derived xenograft tumors rsl3-induced cell death nature 575 nature 593 nature 520 nature 585 nature 572 nature 547 nature 551 nature 489
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- Unsolved mysteries: how does lipid peroxidation cause ferroptosis?
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headline:A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers
description:Targeting ferroptosis, a unique cell death modality triggered by unrestricted lipid peroxidation, in cancer therapy is hindered by our incomplete understanding of ferroptosis mechanisms under specific cancer genetic contexts. KEAP1 (kelch-like ECH associated protein 1) is frequently mutated or inactivated in lung cancers, and KEAP1 mutant lung cancers are refractory to most therapies, including radiotherapy. In this study, we identify ferroptosis suppressor protein 1 (FSP1, also known as AIFM2) as a transcriptional target of nuclear factor erythroid 2-related factor 2 (NRF2) and reveal that the ubiquinone (CoQ)-FSP1 axis mediates ferroptosis- and radiation- resistance in KEAP1 deficient lung cancer cells. We further show that pharmacological inhibition of the CoQ-FSP1 axis sensitizes KEAP1 deficient lung cancer cells or patient-derived xenograft tumors to radiation through inducing ferroptosis. Together, our study identifies CoQ-FSP1 as a key downstream effector of KEAP1-NRF2 pathway and as a potential therapeutic target for treating KEAP1 mutant lung cancers. KEAP1 mutations are frequently observed in NSCLC and lead to drug resistance. Here, the authors show that KEAP1 mutations in lung cancer cells leads to FSP1 upregulation through NRF2, resulting in ferroptosis resistance and radioresistance.
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name:The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, USA
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name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
name:Kadmon Corporation, LLC, New York, USA
name:Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, USA
name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
name:Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, Irvine, USA
name:Kadmon Corporation, LLC, New York, USA
name:Kadmon Corporation, LLC, New York, USA
name:The Barer Institute, Philadelphia, USA
name:Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA
name:The University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences, Houston, USA
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