自噬在卡麦角林治疗中的作用及新机制探索

项目名称： 自噬在卡麦角林治疗中的作用及新机制探索

项目编号： No.81471392

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 吴哲褒

作者单位： 上海交通大学

项目金额： 70万元

中文摘要： 垂体泌乳素腺瘤是最常见的功能性垂体腺瘤，卡麦角林(CAB)为首选治疗。以往针对CAB的作用机制研究集中在激活多巴胺2型受体诱导肿瘤细胞凋亡和PRL分泌减少上，而除此之外的机制仍然不详。目前研究表明，大多数肿瘤化疗药物能诱导自噬。我们前期预实验证实CAB通过抑制mTOR通路诱导垂体肿瘤细胞发生自噬，敲低自噬相关基因p62的表达能减弱CAB的治疗效果。为了明确自噬在CAB治疗中的作用及机制，本课题将进一步在细胞水平和在体水平调控自噬相关基因的表达来观察CAB治疗效果；阐明细胞自噬和凋亡之间的关系；CAB诱导自噬的作用途径；同时，在临床标本上验证关键自噬相关基因的差异表达，指导临床用药。本课题首次研究自噬在CAB治疗中的作用及机制，以及调节自噬用以增强CAB的治疗效果。如果实验成功，将从全新的角度阐明CAB的作用机制，同时将有助于解决耐药泌乳素腺瘤的临床治疗难题，具有深远的临床意义和学术价值。

中文关键词： 自噬；垂体腺瘤；卡麦角林；多巴胺受体；细胞凋亡

英文摘要： Prolactinoma is the most common type of functioning pituitary adenomas and cabergoline (CAB) is the first-line choice of treatment. Previous studies mainly demonstrated that CAB induced the apoptosis of tumor cells and the decrease of PRL secretion through activating dopamine 2 receptor. However, the mechanisms of CAB involving in the regulation of autophagy remain largely unclear. Recent studies indicated that majority of chemotherapeutic drugs could induce autophagy. Our preliminary experiment demonstrated that CAB induced autophagy by inhibiting mTOR signal pathway, moreover, knockdown of autophagy-relative gene p62 could reduce the sensitivity of pituitary adenoma cells to CAB treatment. In order to investigate the function and novel mechanism of autophagy in CAB treatment, we will further confirm in this proposed study ① whether regulation of autophagy-relative genes can change the sensitivity of pituitary adenoma cells to CAB treatment in vitro and in vivo; ② the relationship between tumor cell autophagy and apoptosis induced by CAB; ③ the approach of autophagy induced by CAB; ④ the differential expression of key autophagy-relative genes between clinically sensitive- and resistant- prolactinomas in order to guide the drug therapy. This proposed study for the first time investigates the function and novel mechanism of autophagy in cabergoline treatment and regulation of the autophagy level sensitizes the pituitary tumor cells to CAB treatment. If successful, the findings from this study will give us insight into the novel mechanism of CAB treatment to prolactinomas and provide us a new avenue for treatment of clinical dopamine-resistant prolactinomas, which has far-reaching clinical significance and academic value.

英文关键词： autophagy;pituitary adenoma;cabergoline;dopamine receptor;cell apoptosis