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

IF 15.8 1区 医学 Q1 PHARMACOLOGY & PHARMACY
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
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引用次数: 0

摘要

获得性放射抗性是放疗失败的主要原因,而铁蛋白沉积是放疗过程中细胞死亡的重要机制。虽然在放射耐药细胞的临床样本和细胞模型中都观察到了对铁蛋白沉积的耐受性,但其机制仍未确定。在这里,我们的研究发现,与亲代细胞相比,放射耐药细胞对谷胱甘肽过氧化物酶4(GPX4)抑制剂表现出更大的耐受性,相反,对铁氧化抑制蛋白1(FSP1)抑制剂的敏感性却增加了。这一观察结果表明,FSP1 可能在放射抗性的形成过程中起主导作用。值得注意的是,与 GPX4 基因敲除相比,FSP1 基因敲除在使细胞对放疗再敏感方面表现出更高的效力。为了阐明这种功能转变背后的驱动力,我们进行了一项代谢组学检测,结果显示,在获得性放射抗性细胞中,辅酶Q(CoQ)合成上调,谷胱甘肽合成下调。从机理上讲,辅酶Q的合成是由含arF结构域的激酶3介导的辅酶Q合成酶磷酸化支持的,而溶质运载家族7成员11的下调则导致谷胱甘肽合成的减少。值得注意的是,我们对临床反应数据的回顾性分析进一步证实,在放疗期间额外服用他汀类药物会阻碍 CoQ 的生成,从而有效地使耐放射细胞对辐射再敏感。总之,我们的研究结果表明,在获得放射抗性的过程中,代谢物合成的改变驱动了从 GPX4 到 FSP1 的依赖性转移。此外,我们还提供了通过抑制 FSP1-CoQ 通路逆转放射抗性的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Upregulation of CoQ shifts ferroptosis dependence from GPX4 to FSP1 in acquired radioresistance

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.

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来源期刊
Drug Resistance Updates
Drug Resistance Updates 医学-药学
CiteScore
26.20
自引率
11.90%
发文量
32
审稿时长
29 days
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
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