AZD-8055与自噬抑制剂联合应用促进胆管癌细胞凋亡及抑制转移的机制

项目名称： AZD-8055与自噬抑制剂联合应用促进胆管癌细胞凋亡及抑制转移的机制

项目编号： No.31460303

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 任香善

作者单位： 延边大学

项目金额： 45万元

中文摘要： 胆管癌是来源于胆管上皮细胞的肿瘤，其恶性程度高、预后差。研究表明，PI3K/AKT/mTOR 信号通路介导细胞增殖、分化、凋亡及自噬，在多种恶性肿瘤中起关键的调控作用。胆管癌中mTOR过表达，并与癌的恶性程度及转移相关，提示mTOR的抑制剂在胆管癌治疗中可能起积极作用。目前用于临床的雷帕霉素只能抑制mTORC1，而mTORC2引起AKT的负反馈性磷酸化。新型的mTOR多靶向抑制剂AZD-8055可抑制AKT的磷酸化，减少药物抵抗性。我们前期研究发现， mTOR多靶向抑制剂可诱导胆管上皮细胞自噬。自噬是恶性肿瘤细胞逃避死亡的一种方式,是促肿瘤因素。因此本项目采用AZD-8055与自噬抑制剂chloroquine联合用药，通过多种分子生物学方法及动物实验，探讨其对人胆管癌细胞株及胆管癌动物模型的抑制自噬、促进凋亡作用，阐明其分子机制，为胆管癌的临床治疗提供新的理论基础和实验依据。

中文关键词： 胆管癌；凋亡；自噬；PI3K/AKT/mTOR；抑制剂

英文摘要： Cholangioccarcinoma (CCA) is a malignant neoplasm, that derive from bile duct epithelium with a high degree of malignancy and poor prognosis. The PI3K/AKT/mTOR signaling pathway which regulates normal cellular function, including cell proliferation, differentiation, apoptosis and autophagy, plays critical roles in variety of tumor. Previous studies has shown that the overexpression of mTOR may involve in tumor metastasis . Thus,the mTOR inhibitor may be works as an useful therapeutic strategy in CCA. At present, as one of mTORC1 inhibitor in clinic application , Rapamycin can only repress the expression level of mTORC1. What's more, it is easy to cause drug resistance due to the feedback induction of AKT ser473 phosphorylation.However, AZD-8055 which is a novel multitarget inhibitor of PI3K and mTORC1/C2 can suppresses the phosphorylation of Akt to reduce drug resistance.Our previous studies also demonstrated that multitarget mTOR inhibitor(NVP-BEZ235) can induce autophagy. Autophagy can induce the development of malignant, and also works as one way for malignant cells to escape from death.Therefore, In this study we use the AZD-8055 with autophagy inhibitor chloroquine combination therapy to treat human cholangiocarcinoma cell lines and animal models of cholangiocarcinoma. To explore the potential mechanism of autophagy inhibition and apoptosis promoting by molecular biology method and animal model experiments, and give more trail for further study.

英文关键词： cholangiocarcinoma;apoptosis;autophagy;PI3K/AKT/mTOR inhibiotor