前列腺癌是严重威胁男性健康的重要疾病。本课题组发现，PLK1抑制剂BI6727对前列腺癌细胞及紫杉醇耐药前列腺癌细胞有抑制生长和促进凋亡作用，但机制尚不清楚。进一步发现，PLK1依赖其PBD与NAC1相互作用；NAC1是PLK1的磷酸化底物；且BI6727可使细胞内NAC1蛋白水平降低。据此，我们推测：BI6727对前列腺癌细胞的作用依赖于PLK1-NAC1通路。本课题拟通过细胞和动物实验，进一步验证BI6727抗前列腺癌的有效性；通过点突变、免疫共沉淀等，明确NAC1与PLK1 PBD结合的位点及功能；通过体外激酶反应、质谱鉴定等，明确PLK1磷酸化修饰NAC1的位点及功能；通过免疫组化等，确立由PLK1修饰的NAC1磷酸化水平与前列腺癌分级的关联性。此项目的开展，能够发现一条新的PLK1-NAC1通路，并揭示PLK1的新功能，为临床应用BI6727治疗前列腺癌提供实验和理论依据。

Prostate cancer is one of crucial disease to man. In our previous work, we uncovered that BI6727, an inhibitor of PLK1, could inhibit the growth and promote apoptosis of both regular prostate cancer cells and taxol-resistant prostate cancer cells, but the mechanism is still unclear. In our advanced work, we found that PLK1 interacted with transcription repressors NAC1 depending on its polo-box domain; And NAC1 was one of the phosphorylation substrates of PLK1; In addition, when the activity of PLK1 was prohibited by its inhibitor BI6727, the protein level of NAC1 decreased. So, we think that BI6727 has efficiency on prostate cancer cells depending on PLK1-NAC1 signal pathway. In our further work, we will make sure if BI6727 can treat prostate cancer cells by cell-based in vitro experiment and animal-based in vivo experiment. We will use site mutation，immunoprecipitate and other experiment, to discover the PLK1 binding site in NAC1 and the function of this site; we will also use kinase assay and mass spectrum detection to find out the site that PLK1 phosphorylates NAC1 and uncover the function of this phosphorylation modification. Finally, we will use immunohistochemical staining to analyse the relationship between phosphorylation level of NAC1 by PLK1 and the grade of prostate cancer. This project will reveal a new pathway, PLK1-NAC1 pathway, and find the novel function of PLK1. It will also provide experimental support and new mechanism for BI6727 treating prostate cancer.