基于靶向抑制Aurora B激酶探讨丹参酮IIA干预口腔鳞癌的分子机制

Oral squamous cell carcinoma (OSCC) is one of the leading causes of cancer-related death in China. Insufficiency of the efficient therapeutic agents in patients with advanced OSCC is a major obstacle for clinical treatment. Previous studies suggested that high expression of Aurora B kinase is involved in the tumorigenesis of OSCC. Here, using the virtual computational screening of the Traditional Chinese Medicine Database, we identified that Tanshinone IIA as an Aurora B kinase inhibitor. We will focus on the molecular mechanism of Tanshinone IIA-mediated Aurora B suppression via performing of a series of in vitro and ex vivo assays. Additionally, we will construct the xenograft mouse model and patient-derived xenograft mouse model to investigate the in vivo anti-OSCC efficacy of Tanshinone IIA. Overall, this study will help us to understand the novel antitumor mechanism of Traditional Chinese Medicine, and provide an instructive framework for subsequent discovery of novel kinase inhibitors.

口腔鳞癌是我国高发致死性恶性肿瘤，中晚期患者缺乏有效治疗药物，是口腔鳞癌临床治疗亟待解决的。研究发现Aurora B激酶的高表达与口腔鳞癌的发生发展密切相关，前期工作中我们借助超级计算机模拟筛选为平台，从传统抗肿瘤中药库中筛选出Aurora B激酶潜在抑制剂丹参酮IIA，能有效缓解口腔癌前病变，但作用机制不明。本项目拟以计算机模拟对接为指导，从分子、细胞水平阐明丹参酮IIA抑制Aurora B激酶活性的分子机制，并借助裸鼠移植瘤和病人肿瘤组织来源的移植瘤模型体内验证丹参酮IIA抗口腔鳞癌的药理作用。本研究将阐明丹参酮IIA的抗肿瘤机制，拓宽我们对中药抗肿瘤机制的认识，为建立抗肿瘤中药库，筛选其他激酶抑制剂提供新思路。

Aurora B激酶的高表达与多种肿瘤的发生发展密切相关，靶向Aurora B激酶的小分子抑制剂研发已成为抗肿瘤药物研发的热点。丹参酮IIA是中药丹参的重要活性成分，具有抗炎、抗病毒及抗肿瘤等多种生物学活性。本项目利用计算机分子模拟发现，丹参酮IIA可靶向抑制Aurora B蛋白激酶。以口腔鳞癌（OSCC）为研究模型，利用体内外分子细胞实验阐明了丹参酮IIA靶向Aurora B抑制OSCC的分子机制，丹参酮IIA剂量依赖性抑制OSCC细胞增殖，细胞存活，软琼脂克隆形成，并促进OSCC细胞发生凋亡。分子机制研究表明：丹参酮IIA可与Aurora B蛋白激酶相互结合并与ATP竞争结合于Aurora B蛋白激酶ATP结合结构域，导致OSCC有丝分裂障碍和多核细胞形成并最终诱导细胞凋亡。体内实验结果表明：丹参酮IIA抑制多株OSCC细胞异种移植瘤的生长，并下调Aurora B信号通路激活。本研究创新性发现丹参酮IIA可作为Aurora B激酶小分子抑制剂发挥抗OSCC活性，发现靶向抑制Aurora B激酶可在体内外抑制OSCC的多种恶性表型。本项目的创新性发现对丹参酮IIA的临床转化意义重大，为靶向Aurora B的OSCC临床治疗提供新的思路。