转移和多药耐药是导致肿瘤患者治疗失败和死亡的主要原因，P-glycoprotein（P-gp）高表达是导致癌细胞发生多药耐药的关键原因。大量证据显示癌细胞获得多药耐药的同时常伴随着侵袭转移能力的增强，但是分子机制不明。前期研究证实P-gp通过与Anxa2相互作用促进了癌细胞的侵袭。随后又发现Rack1和Src是P-gp的结合蛋白质，而且Rack1表达下降抑制了细胞的侵袭和Anxa2的磷酸化。由于已知Src是Anxa2的上游激酶，也是Rack1的结合蛋白质，因此推测Rack1和Src介导了耐药肿瘤细胞的侵袭。本课题拟采用免疫共沉淀、免疫荧光、Western blotting、siRNA等实验技术，研究Rack1和Src对P-gp的活性和细胞侵袭的作用；明确三者的相互作用模式以及对MAPK和Rho/Rac信号通路的影响，阐明P-gp促进耐药肿瘤细胞侵袭转移能力增强的分子机制。

Metastasis and multi-drug resistance (MDR) are major causes of treatment failure and death for cancer patients. P-glycoprotein (P-gp) is one of the key proteins that mediate multidrug resistance in cancer cells. Accumulating evidences demonstrated that acquirement of MDR often associated with enhanced invasion of cancer cells; however, the detailed mechanism remains unclear. In addition to function as a drug pump, we previously showed that P-gp also promotes invasiveness of cancer cells through interaction with Anxa2. Subsequently, we identified Rack1 and Src are novel binding proteins of P-gp, and small interference RNA mediated knockdown of Rack1 significantly inhibited invasion of MDR cancer cells as well as phosphorylation of Anxa2. As Src is well known as an upstream kinase of Anxa2, and a binding partner of Rack1, we hypothesize that Rack1 and Src may play pivotal roles in invasion of MDR cancer cells. In this study, we plan to use co-immunoprecipitation, immunofluorescence, Western blotting and siRNA methods to investigate the potential effect of Rack1 and Src on P-gp activity, Anxa2 phosphorylation and MDR cancer cells invasion, and we also want to clarify the details of how P-gp interacts with Rack1 and Src. In addition, we will also examine the potential effect of these proteins on activation of MAPK and Rho/Rac signaling pathway. Our study will illustrate the molecular mechanism of enhancement of cancer cell invasion induced by multidrug resistance.