mTOR信号通路介导的自噬在替莫唑胺治疗垂体腺瘤中的作用及机制研究

Temozolomide (TMZ) has recently been shown to have significant activity as a sole salvage therapy for treatment of refractory pituitary adenomas (PAs), which resistant to standard therapy including neurosurgery, radiotherapy and pharmacological treatment. However, not all PAs showed response to TMZ, and some patients can acquire TMZ resistance after treatment. Autophagy, a self-defense mechanism, has been found to be associated with chemotherapy resistance in many tumor including hepatocellular carcinoma, Non-Small Cell Lung Cancer Cells, chronic myeloid leukemia and glioma..In the previous study, we found that the expression of autophagy-related protein (LC3) is increased significantly and the mTOR signaling pathway is supressed in PA patients after TMZ treatment. We also proved that TMZ inhibites the mTOR signaling pathway and induces autophagy in GH3 cell line, furthermore, inhibition of autophagy improves the efficacy of TMZ in GH3 cells through inducing apoptosis and reducing autophagy. In order to investigate the function and novel mechanism of autophagy in TMZ treatment for PA, we intend to 1) further confirm the role of autophagy in patients with PA refractory to TMZ treatment, investigate the relationship between TMZ-induced autophagy and mTOR signaling pathway; 2) Assess the effects of induction of autophagy and inhibition of autophagy on the efficacy of TMZ on PA cells in vitro and in vivo; 3) investigate the relationship between tumor cell autophagy and apoptosis induced by TMZ; 4) explore whether TMZ induces autophagy in PA cells via regulating mTOR signaling pathway. We hope that this study could provide a novel insight into potential therapeutic strategies for treatment of PAs refractory to conventional treatment and TMZ.

替莫唑胺（TMZ）是目前治疗难治性垂体腺瘤(pituitary adenoma, PA)唯一有效的化疗药物。但是，并非所有的PA对TMZ敏感，还有部分PA在TMZ治疗后产生耐药。我们前期研究提示： 在TMZ治疗PA中，通过mTOR信号通路诱导了PA细胞发生自噬，通过抑制自噬能增加PA细胞对TMZ的敏感性。我们拟进一步：1)在临床方面，继续收集对TMZ治疗不敏感的PA标本，验证自噬在TMZ治疗PA中的作用，以及和mTOR的关系；2)从细胞和在体水平通过诱导和抑制细胞自噬，探讨自噬在TMZ治疗PA中的作用，阐明自噬和凋亡之间的关系，以及TMZ通过mTOR调节自噬的作用途径。本课题首次探讨了自噬在TMZ治疗PA中的作用，以及调节自噬对TMZ的疗效的影响，以期从自噬角度来提高PA对TMZ的敏感性，解决TMZ耐药问题，为难治性垂体腺瘤的治疗提供新的治疗方法和理论依据。

在临床方面，收集了6例对TMZ治疗不敏感的PA标本，验证了自噬在TMZ治疗PA中的作用，以及和mTOR的关系。从细胞和在体水平，通过诱导和抑制细胞自噬，探讨了自噬在TMZ治疗PA中的作用，阐明自噬和凋亡之间的关系，以及TMZ通过mTOR调节自噬的作用途径。本课题首次探讨了自噬在TMZ治疗PA中的作用，以及调节自噬对TMZ的疗效的影响，以期从自噬角度来提高PA对TMZ的敏感性，解决TMZ耐药问题，为难治性垂体腺瘤的治疗提供新的治疗方法和理论依据。