DJ-1调控的XLF/XRCC4异二聚体在戒酒药双硫仑增敏顺铂抗卵巢癌活性中的作用机制研究

顺铂是目前临床治疗卵巢癌的一线化疗药物，但存在着化疗敏感性不佳的问题，亟需发现提高顺铂抗卵巢癌活性的新策略。申请人在前期研究中，通过上市药物库联合顺铂筛选发现，戒酒药物双硫仑与顺铂合用能极其显著地增强顺铂的抗卵巢癌活性。我们进一步研究发现，DJ-1蛋白是双硫仑的直接分子靶点，在双硫仑增敏顺铂抗卵巢癌活性中发挥了关键作用。分子机制上，双硫仑通过结合并抑制DJ-1调控的DNA修复蛋白复合物XLF/XRCC4，降低了顺铂引起DNA损伤的修复过程。本项目将在此基础上进一步明确双硫仑体内外增敏顺铂抗卵巢癌活性的作用，阐明DJ-1调控XLF/XRCC4异源二聚体发挥双硫仑增敏顺铂抗肿瘤活性的分子机制。本项目的顺利开展，不仅能从老药新用的角度，为临床克服卵巢癌对顺铂耐药提供一种可快速转化应用的新合用方案，而且有望揭示DJ-1调控DNA损伤修复的新分子机制，故具有重要的理论和临床转化双重价值。

Cisplatin is the first-line chemotherapeutic drug for ovarian cancer in the clinical treatment. Given the poor response in clinic, it is urgent to discover new strategies to improve the anti-ovarian cancer effect of cisplatin. In our preliminary study of screening the drug library, we found that disulfiram can significantly enhance the anti-ovarian effect of cisplatin. Further study indicated that DJ-1 protein is the direct molecular target of disulfiram, which plays a key role in disulfiram enhance the anti-ovarian cancer effect of cisplatin. Moreover, disulfiram covalently binds DJ-1 and inhibits the DJ-1-driven DNA damage repair protein complex XLF/XRCC4 formation, and eventually results in the deficiency of DNA repair process. This project will further clarify the role of disulfiram in enhancing the anti-ovarian cancer effect of cisplatin in vitro and in vivo and will also clarify the molecular mechanism of DJ-1 regulates the XLF/XRCC4 heterodimer. This project can not only expand the new application of disulfiram in the clinical treatment of ovarian cancer, but also uncover a novel molecular mechanism of DJ-1 regulating DNA damage repair.