PP2A结构亚基Aalpha在前列腺癌中的表达机制及抗癌功能分析

Protein serine/threonine phosphatase-2A (PP2A) is one of the major eukaryotic phosphatases, contributing more than 50% serine/threonine phosphatase activity. The holoenzyme of PP2A is a heterogenous trimer consisting of a scaffold subunit A, a catalytic subunit C and a regulatory subunit R. The A subunit provides a platform for both C and R subunits to bind, thus acting as a key component for specific PP2A activity. The A subunit exists in two isoforms: Aα and Aβ. Mutation or downregulation of the A subunits causes various types of cancer including lung, breast and brain cancer. Thorought these studies, however,it remains unknown if a change in the expression levels of the A subunits of PP2A would affect the tumorigenesity in the prostate cancer. In this regard, our recent studies have revealed that the Aα promoter is actively regulated by numerous transcription factors including CREB, ETS-1, AP-2α and SP-1. Moreover, we demonstrated that in prostate cancer cells, DU145,a very low level of Aα was detected. Associated with this low level of Aα expression, CREB expression is barely detectable. Based on these results, we hypothesize that CREB may be a key transcription factor, regulating the expression level of PP2A-Aα, and the expression level of PP2A-Aα may be linked to tumorigenesity activity of the prostate cancer cells. In the present application, we propose to use prostate cancer cells and nude mice to test our hypothesis and obtain the answers to the following questions: 1) Is CREB a key regulator for PP2A-Aα expression ? 2) Is the expression level of PP2A-Aα related to the tumorigenic activity of DU145 cells ? The obtained results will not only illustrate the regulatory mechanisms by which PP2A-Aα is regulated in prostate cancer cells but also determine if the expression level of PP2A-Aα is linked to the ability of tumor promotion in these cells. Togetrher, our study will shed light to possible new therapeutic strategy for prostate cancer patients.

PP2A是真核生物中十分重要的蛋白磷酸酶。PP2A全酶由催化亚基（C）、结构亚基（A）和调节亚基(B)组成异三聚体。A亚基提供C和B亚基结合的平台，是细胞内特异PP2A活性的必要组成部分。结构亚基编码基因突变或下调导致一系列的癌变，如肺癌、乳腺癌和脑癌等。然而结构亚基的表达与前列腺癌形成之间的关系尚缺乏研究，本小组最近对结构亚基Aα基因启动子的分析表明，PP2A-Aα基因受多个转录因子调控。在前列腺癌细胞DU145中，PP2A-Aα和控制其表达的转录因子CREB都显著下调。本项目拟以DU145细胞系和裸鼠动物模型为材料来探讨：1）确定在DU145中，CREB是否是调控PP2A-Aα的主要转录因子？2）阐明PP2A-Aα的表达水平是否与DU145细胞的致癌能力密切相关？本项目将进一步阐明PP2A-Aα表达的控制机制，并确定其表达水平与其抗癌能力的关系，从而对前列腺癌的治疗提供新的切入点。

PP2A是真核生物中十分重要的蛋白磷酸酶。其全酶由催化亚基C，结构亚基A和调节亚基B组成异三聚体。A亚基提供C和B亚基结合的平台，是细胞内特异PP2A活性的必要组成部分。结构亚基编码基因突变或下调导致一系列的癌变，如：肺癌、乳腺癌和脑癌等。本项目在国家基金委的资助下，首次探讨了PP2A结构亚基Aα的表达与前列腺癌形成之间的关系。以前列腺癌细胞DU145和LNCaP为体外检测系统，裸鼠为体内检测系统，并运用多种分子细胞生物学和生物化学方法，进行了一系列的实验研究，对PP2A结构亚基Aα与前列腺癌形成之间的关系，阐明了3个方面的重要信息。首先，我们的工作表明在前列腺癌细胞DU145和LNCaP中，CREB是调节Aα的主要转录因子；其次，我们证明了在上述癌细胞中，除CREB外，Aα的表达水平受ETS-1，AP-2α和SP1/SP3的调节。最后，我们进一步确定了在DU145细胞中过表达外源的CREB和Aα，抑制上述前列腺癌细胞的致癌能力，且抑制能力是Aα大于CREB。这些结果表明CREB和Aα均可以作为治疗前列腺癌的新的切入点，为其临床转化医学研究提供了有力论据和重要基础。本课题资助发表了14篇SCI科学论文，2篇论文专著，及正在发表中的3篇研究论文。本课题帮助培养了1名青年教师，6名博士研究生和15硕士研究生。