干扰DJ-1蛋白同源二聚体功能发挥抗肿瘤作用的分子机制研究

DJ-1 is a multi-functional protein that plays important role in promoting cancer cell proliferation and survival, and is critical in oxidative stress-regulated cellular activity through mechanisms unknown. Our findings suggested that DJ-1 homodimer might be the functional unit underlying DJ-1 associated activities. Based on the structure of DJ-1 protein, we found that DJHDI-1, a small molecule that effectively interrupt the formation of DJ-1 homodimer, showed significant anti-tumor effect both in vitro and in vivo, possibly through inhibiting DJ-1 activity and increasing its degradation. Based on previous findings and using DJHDI-1 as a probe, our study will focus on the mechanism of DJ-1 homodimer-mediated oxidative stress and elucidate the role of ubiquitination-degradation of DJ-1 monomers in the inhibition of cancer cells by specifically targeting the formation of DJ-1 homodimers. Our study not only will advance our knowledge of DJ-1 homodiers and oxidative stress-related modulations, but also provide strategies for the development of novel anti-tumor drugs targeting DJ-1 activity.

DJ-1蛋白作为一个多功能蛋白，是氧化应激调控网络中的关键节点，在促进肿瘤细胞增殖及存活中发挥了重要作用，但具体机制并不明确。我们研究表明DJ-1蛋白同源二聚体可能是其发挥生物学活性的功能单元。基于DJ-1蛋白结构信息，我们发现可有效干扰DJ-1蛋白同源二聚体的小分子化合物DJHDI-1，具有较强的体内外抗肿瘤活性，并可能与其干扰DJ-1蛋白生物学活性及促进其单体的降解相关。本项目将在此基础上，进一步以DJHDI-1作为分子探针，明确其通过干扰DJ-1蛋白二聚体形成发挥抗肿瘤活性的模式，研究DJ-1蛋白二聚体对肿瘤细胞内氧化应激信号网络的调控机制，并探索DJ-1蛋白单体泛素化降解的分子机制及其在抗肿瘤活性中的作用。本项目的开展，不仅将阐明DJ-1蛋白二聚体的生物学意义，丰富氧化应激调控的理论体系；还将为DJ-1作为抗肿瘤药物靶点提供理论依据，并为针对此靶点研发原创性抗肿瘤药物提供全新思路。

DJ-1蛋白作为一个多功能蛋白，是氧化应激调控网络中的关键节点，在促进肿瘤细胞增殖及存活中发挥了重要作用，但具体机制并不明确。我们研究表明DJ-1蛋白同源二聚体是其发挥生物学活性的功能单元。基于DJ-1蛋白结构信息，我们发现可有效干扰DJ-1蛋白同源二聚体的小分子化合物DJHDI-1，具有较强的体内外抗肿瘤活性，并与其干扰DJ-1蛋白生物学活性及促进其单体的降解相关。本项目的研究工作不仅阐明了DJ-1蛋白二聚体的生物学意义，丰富氧化应激调控的理论体系；还为DJ-1作为抗肿瘤药物靶点提供了理论依据，并为针对此靶点研发原创性抗肿瘤药物提供了全新思路。研究内容发表SCI论文3篇，授权发明专利5项，发表DJ-1相关外文专著1本，并获得教育部自然科学二等奖奖励1次。