棉酚通过抑制线粒体APE1活性克服宫颈癌放疗抵抗的机制研究

APE1 is a nucleoprotein with both DNA repair and redox activity, which plays a crucial role in oxidative stress in response to radiotherapy. Previous researches found that there were high expression of extranuclear APE1 in tumors such as cervical cancer, which is closely related to radiotherapy resistance. However the mechanism has not been clarified. Our preliminary study found firstly that gossypol could play important role of anti-tumor and chemotherapy sensitivity enhancement by inhibiting double function of APE1. According to the results of our previous studies and the latest literature, we propose that the gossypol can inhibit mitochondrial APE1 function so as to overcome the radiotherapy resistance mediated by mitochondrial oxidative stress in cervical cancer. To test this possibility, we used plasmid transfection and RNA interference, a specific inhibitor of APE1, studied from different levels of molecular, subcellular, cellular and animal, focusing on the role of APE1 in mitochondrial oxidative stress mediated radiotherapy resistance, try to explore the feasibility of overcoming radiotherapy resistance by inhibiting function of mitochondrial APE1 with gossypol in cervical cancer. This study will open up a new research field of APE1. It not only helps to elucidate the biological significance of APE1 subcellular localization, but also to reveal the radiotherapy resistance mechanisms of cervical cancer, has the extremely vital significance to find new therapeutic targets which overcome radiotherapy resistance of cervical cancer.

APE1是具有DNA损伤修复和氧化还原双功能的核蛋白，在放疗等诱导的氧化应激反应中具有核心作用。前期研究发现在宫颈癌等肿瘤中核外APE1高表达与放疗耐受密切相关，而机制尚不清楚。我们前期研究中首次发现棉酚可抑制APE1的双功能从而发挥抗肿瘤及化疗增敏作用。根据前期研究结果及最新文献复习，我们提出棉酚可通过抑制线粒APE1功能从而克服线粒体氧化应激介导的宫颈癌放疗抵抗。为了验证这一假设，我们运用质粒转染、RNA干扰、特异性抑制等手段，从分子、亚细胞、细胞和动物水平多层次进行研究，着重阐明APE1在线粒体氧化应激中的作用及其介导肿瘤放疗抵抗的机制，探寻棉酚通过抑制线粒体APE1功能从而克服宫颈癌放疗抵抗的可行性。本项目开辟了APE1研究的一个崭新领域，不仅有助于系统阐明APE1亚细胞定位的生物学意义，而且对于揭示宫颈癌放疗耐受机制，探寻克服宫颈癌放疗抵抗的治疗靶点均具有十分重要的意义。