PAK6介导的内质网应激性细胞自噬在复发性前列腺癌中的作用及机制

Prostate cancer is the most frequently diagnosed malignancy in men. The transformation from androgen-dependent to androgen-independent is the dominant feature of lethal prostate cancer, which leads to recurrency of prostate cancer. There is no effective therapeutic strategy for recurrent prostate caner untill now. A variety of factors could disturb the homeostasis of endoplasimic reticulum (ER), called ER stress. However, ER stress that can not be rescued results in autophagy(ER stress autophagy, ERSA). ERSA plays important roles in tumor, while the precise mechanism was largely unknown. PAK6, as the member of p21 activated kinase family, its expression is positive relative with the process of prostate cancer, especially in recurrent prostate cancer after androgen ablation therapy. Previously, we found that endogenous expression of p21 activated kinase 6 (PAK6) was up-regulated upon ER stress. Meanwhile, PAK6 led to the conversion of LC3-I to LC3-Ⅱ, a commonly used marker of autophagy. These observations indicate that PAK6 might play important role in prostate cancer through triggering ERSA. In this project, the tissue microarray and in vivo imaging technology were used to detect the regulatory roles of PAK6-mediaed ERSA in recurrent prostate cancer growth and development.And the mechanism of PAK6-mediated ERSA in prostate cancer will be discovered. The accomplishment of this program will propose a novel mechanism accounting for PAK6-mediated ERSA in prostate tumor growth and development, as well as providing the scientific basis for the molecular targeted therapy of PAK6 in prostate cancer.

前列腺癌是男性恶性肿瘤的第一杀手，由雄激素依赖性转变为非依赖性从而导致前列腺癌复发是致死性前列腺癌的根本特性，而复发性前列腺癌目前尚无有效的治疗方案，其防治策略成为医学界研究的重要命题。研究证明，内质网应激性细胞自噬（ER stress autophagy, ERSA）在肿瘤的生理病理过程中发挥重要作用。临床资料显示，PAK家族成员PAK6在复发性前列腺癌中呈高表达。我们前期研究发现，PAK6在内质网应激发生的情况下内源性表达增加，并引起自噬标志蛋白的改变，提示PAK6诱导内质网应激性细胞自噬发生，并且可能通过ERSA调控复发性前列腺癌的发生发展。本项目将结合临床研究，利用组织芯片技术和小动物活体成像技术，研究PAK6促进ERSA的调控过程及其生物学功能；揭示PAK6介导的ERSA在复发性前列腺癌发生发展中的作用及分子机制。研究结果将为PAK6在恶性雄激素肿瘤的分子靶向治疗奠定基础。