Xu Lin , Qingyi Zhang , Qi Li , Jun Deng , Shuying Shen , Muhu Tang , Xianghua Ye , Cong Ji , Yuhong Yang , Yuxiao Chen , Liping Zeng , Jiangang Zhao , M.B.N. Kouwenhoven , Don Eliseo Lucero-Prisno III , Junjie Huang , Yangling Li , Bo Zhang , Jian Hu
{"title":"在获得性放射抗药性中,CoQ的上调将对铁氧化酶的依赖从GPX4转移到了FSP1","authors":"Xu Lin , Qingyi Zhang , Qi Li , Jun Deng , Shuying Shen , Muhu Tang , Xianghua Ye , Cong Ji , Yuhong Yang , Yuxiao Chen , Liping Zeng , Jiangang Zhao , M.B.N. Kouwenhoven , Don Eliseo Lucero-Prisno III , Junjie Huang , Yangling Li , Bo Zhang , Jian Hu","doi":"10.1016/j.drup.2023.101032","DOIUrl":null,"url":null,"abstract":"<div><p>Acquired radioresistance is the primary contributor to treatment failure of radiotherapy, with ferroptosis is identified as a significant mechanism underlying cell death during radiotherapy. Although resistance to ferroptosis has been observed in both clinical samples of radioresistant cells and cell models, its mechanism remains unidentified. Herein, our investigation revealed that radioresistant cells exhibited greater tolerance to Glutathione Peroxidase 4 (GPX4) inhibitors and, conversely, increased sensitivity to ferroptosis suppressor protein 1 (FSP1) inhibitors compared to their sensitive counterparts. This observation suggested that FSP1 might play a dominant role in the development of radioresistance. Notably, the knockout of FSP1 demonstrated considerably superior efficacy in resensitizing cells to radiotherapy compared to the knockout of GPX4. To elucidate the driving force behind this functional shift, we conducted a metabolomic assay, which revealed an upregulation of Coenzyme Q (CoQ) synthesis and a downregulation of glutathione synthesis in the acquired radioresistance cells. Mechanistically, CoQ synthesis was found to be supported by aarF domain containing kinase 3-mediated phosphorylation of CoQ synthases, while the downregulation of Solute carrier family 7 member 11 led to decreased glutathione synthesis. Remarkably, our retrospective analysis of clinical response data further validated that the additional administration of statin during radiotherapy, which could impede CoQ production, effectively resensitized radioresistant cells to radiation. In summary, our findings demonstrate a dependency shift from GPX4 to FSP1 driven by altered metabolite synthesis during the acquisition of radioresistance. Moreover, we provide a promising therapeutic strategy for reversing radioresistance by inhibiting the FSP1-CoQ pathway.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8000,"publicationDate":"2023-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1368764623001152/pdfft?md5=e217dcb3a41316b0cdbe650ffa4eb31d&pid=1-s2.0-S1368764623001152-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Upregulation of CoQ shifts ferroptosis dependence from GPX4 to FSP1 in acquired radioresistance\",\"authors\":\"Xu Lin , Qingyi Zhang , Qi Li , Jun Deng , Shuying Shen , Muhu Tang , Xianghua Ye , Cong Ji , Yuhong Yang , Yuxiao Chen , Liping Zeng , Jiangang Zhao , M.B.N. Kouwenhoven , Don Eliseo Lucero-Prisno III , Junjie Huang , Yangling Li , Bo Zhang , Jian Hu\",\"doi\":\"10.1016/j.drup.2023.101032\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Acquired radioresistance is the primary contributor to treatment failure of radiotherapy, with ferroptosis is identified as a significant mechanism underlying cell death during radiotherapy. Although resistance to ferroptosis has been observed in both clinical samples of radioresistant cells and cell models, its mechanism remains unidentified. Herein, our investigation revealed that radioresistant cells exhibited greater tolerance to Glutathione Peroxidase 4 (GPX4) inhibitors and, conversely, increased sensitivity to ferroptosis suppressor protein 1 (FSP1) inhibitors compared to their sensitive counterparts. This observation suggested that FSP1 might play a dominant role in the development of radioresistance. Notably, the knockout of FSP1 demonstrated considerably superior efficacy in resensitizing cells to radiotherapy compared to the knockout of GPX4. To elucidate the driving force behind this functional shift, we conducted a metabolomic assay, which revealed an upregulation of Coenzyme Q (CoQ) synthesis and a downregulation of glutathione synthesis in the acquired radioresistance cells. Mechanistically, CoQ synthesis was found to be supported by aarF domain containing kinase 3-mediated phosphorylation of CoQ synthases, while the downregulation of Solute carrier family 7 member 11 led to decreased glutathione synthesis. Remarkably, our retrospective analysis of clinical response data further validated that the additional administration of statin during radiotherapy, which could impede CoQ production, effectively resensitized radioresistant cells to radiation. In summary, our findings demonstrate a dependency shift from GPX4 to FSP1 driven by altered metabolite synthesis during the acquisition of radioresistance. Moreover, we provide a promising therapeutic strategy for reversing radioresistance by inhibiting the FSP1-CoQ pathway.</p></div>\",\"PeriodicalId\":51022,\"journal\":{\"name\":\"Drug Resistance Updates\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":15.8000,\"publicationDate\":\"2023-12-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1368764623001152/pdfft?md5=e217dcb3a41316b0cdbe650ffa4eb31d&pid=1-s2.0-S1368764623001152-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Resistance Updates\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1368764623001152\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Resistance Updates","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1368764623001152","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Upregulation of CoQ shifts ferroptosis dependence from GPX4 to FSP1 in acquired radioresistance
Acquired radioresistance is the primary contributor to treatment failure of radiotherapy, with ferroptosis is identified as a significant mechanism underlying cell death during radiotherapy. Although resistance to ferroptosis has been observed in both clinical samples of radioresistant cells and cell models, its mechanism remains unidentified. Herein, our investigation revealed that radioresistant cells exhibited greater tolerance to Glutathione Peroxidase 4 (GPX4) inhibitors and, conversely, increased sensitivity to ferroptosis suppressor protein 1 (FSP1) inhibitors compared to their sensitive counterparts. This observation suggested that FSP1 might play a dominant role in the development of radioresistance. Notably, the knockout of FSP1 demonstrated considerably superior efficacy in resensitizing cells to radiotherapy compared to the knockout of GPX4. To elucidate the driving force behind this functional shift, we conducted a metabolomic assay, which revealed an upregulation of Coenzyme Q (CoQ) synthesis and a downregulation of glutathione synthesis in the acquired radioresistance cells. Mechanistically, CoQ synthesis was found to be supported by aarF domain containing kinase 3-mediated phosphorylation of CoQ synthases, while the downregulation of Solute carrier family 7 member 11 led to decreased glutathione synthesis. Remarkably, our retrospective analysis of clinical response data further validated that the additional administration of statin during radiotherapy, which could impede CoQ production, effectively resensitized radioresistant cells to radiation. In summary, our findings demonstrate a dependency shift from GPX4 to FSP1 driven by altered metabolite synthesis during the acquisition of radioresistance. Moreover, we provide a promising therapeutic strategy for reversing radioresistance by inhibiting the FSP1-CoQ pathway.
期刊介绍:
Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation.
Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective.
*Expert reviews in clinical and basic drug resistance research in oncology and infectious disease
*Describes emerging technologies and therapies, particularly those that overcome drug resistance
*Emphasises common themes in microbial and cancer research