PAK5/beta-catenin信号通路在肝癌细胞耐药中的作用及机制研究

PAK5是一类丝氨酸/苏氨酸蛋白激酶，近年来的研究发现PAK5与肿瘤的发生发展密切相关。我们前期研究结果显示PAK5能增强肝癌细胞的抗凋亡功能并且产生对顺铂的抗性，但具体作用机制及其调控模式尚不清楚。我们初步研究发现PAK5可以促进耐药基因ABCB1的表达和beta-catenin的磷酸化，据此提出科学假说：PAK5通过磷酸化其底物beta-catenin，进而促进其核转位，入核的beta-catenin与TCF形成转录复合物进一步结合到ABCB1启动子上激活其转录从而引起肝癌细胞对药物的耐受。. 本项目拟以肝癌标本、培养的细胞及裸鼠为研究对象，从分子、细胞与整体水平研究PAK5介导肝癌细胞耐药的机制。预期研究结果将阐明肝癌耐药的机制，揭示PAK5-beta-catenin通路是调控肝癌细胞耐药的新的信号通路；为肝癌的分子靶向治疗提供理论依据和治疗靶点。

p21-activated kinases 5 (PAK5) is a serine/threonine kinase and has recently attracted considerable attention as that it is found closely related with carcinogenesis and tumor progression. Our previous study showed that PAK5 could promote the anti-apoptosis properties and enhance the resistance to cisplatin of hepatocelluar carcinoma cells, but the exact regulatory mechanism is unknown. Our preliminary data showed that PAK5 could promote the expression of ABCB1 and the phosphorylation of beta-catenin. On the basis of these findings, we propose the hypothesis that PAK5 phosphorylates beta-catenin and promotes its nuclear localization. The beta-catenin in nuclear together with TCF can bind to the promoter of ABCB1 and activate the transcription of ABCB1, ultimately induce the drug resistance of hepatocelluar carcinoma cells. Thus, by using hepatocelluar carcinoma specimens, cultured hepatocelluar carcinoma cells and nude mice, we intend to study the mechanism underlying the PAK5 mediated drug resistance to hepatocelluar carcinoma at molecular, cellular and animal levels. Our expected results will not only elucidate the drug resistance mechanism and discover a new signal pathway account for of drug resistance to hepatocelluar carcinoma, but also provide valuable idea for finding potential targets for molecular therapy of hepatocelluar carcinoma.