Cell Cycle and Senescence Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged 1 in Prostate Cancer by Enhancing Cyclin B 1 Expression via Akt Phosphorylation

The Jagged1, a Notch signaling pathway ligand, had been shown to have a positive correlation with prostate cancer development. Our study for Jagged1 expression in 218 prostate cancer tissue samples also supports this conclusion.However, the detailedmolecularmechanismof Jagged1 in promoting the progression of prostate cancer is still unclear. Through cell proliferation examination, androgen receptor (AR) was found to promote the oncogenic function of Jagged1 to enhance the cell proliferation rate by comparing four prostate cancer cell lines, LNCaP, LAPC4, DU145, and PC3, which was further validated through analyzing the survival of 118 patients treated with androgen-deprivation therapy (ADT) with different expression levels of Jagged1 and AR. More importantly, our data showed that Jagged1 combined with AR could increase the phosphorylation level of Akt and, in turn, phosphorylated Akt plays an important role in regulating the expression level of cyclin B1 by interacting with AR and increasing the transcriptional activity of AR. These data indicate that prostate cancer progression regulated by Jagged1 can be dramatically enhanced by combining with AR through promoting Akt activity. Implications: This study could benefit our clinical treatments for patients with prostate cancer with overexpressed Jagged1 by targeting AR and Akt. Mol Cancer Res; 1–13. 2014 AACR. Introduction Prostate cancer is one of the most commonly diagnosed noncutaneous cancers and a leading cause of cancer-related deaths in American men (1). Although several new therapeutics have been approved, efficient treatments still lack for the advanced prostate cancer, such as castration-resistant prostate cancer (CRPC) and prostate cancer with metastasis (2). To obtain better outcomes for patients with prostate cancer, there is an urgent need for better understanding the detailed molecular pathways in the progression of prostate cancer to develop some new treatments. Prostate cancer is an androgen-dependent disease, and these actions are dependent on the androgen receptor (AR). AR is expressed inmany prostate cancer cells and has been proved to play a significant role in the tumorigenesis andmetastasis of prostate cancer (3, 4). Inhibiting the activities of AR is an important direction in the treatment of primary prostate cancer to prevent tumor progression (5, 6). A large body of evidence implicates that androgen signaling is modified after androgen-deprivation therapy (ADT), and AR overexpression is the major cause of CRPC (7–10). That is, AR still plays a critical role in CRPC development. Except for AR, proteins that participate in a variety of other cell signaling pathways can also affect prostate cell death or survival (11). Many cell signaling pathways play different roles in the development and progression of prostate cancer, such as NF-kB, JAK/STAT, MAPK, Wnt, PI3K/Akt, and Notch signaling. Among these, the Notch signaling pathway, which is present in most multicellular organisms, plays a role in cancer metastasis by governing embryonic development, maintaining tumor stemness, modulating the epithelial-to-mesenchymal transition (EMT), and affecting tumor angiogenesis processes (12– 14). Several studies have demonstrated that the Notch signaling pathway is required for prostatic growth and plays a key role in the progression andmetastasis of prostate cancer (15–17). It had been proved that the expression of both Notch receptors and their ligands would be upregulated in many prostate cancer cells compared with normal prostate cells (18–21). In mammals, except for the four Notch receptor members (Notch1-4), five Notch ligands have been identified so far, including Delta-like 1/3/4 (Dll 1/3/4) and Jagged1/2 (17, 22). Jagged1 was found to be highly expressed in most prostate cancer cells and increased in localized prostate cancer compared with benign prostate hyperplasia in the Authors' Affiliations: Departments of Urology, Day Ward, and Pathology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Corresponding Author: Jun Qi, Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Phone: 86-21-2507-8080; Fax: 86-21-6579-3206; E-mail: junqi_xh@126.com doi: 10.1158/1541-7786.MCR-13-0545 2014 American Association for Cancer Research. Molecular Cancer Research www.aacrjournals. org OF1 on June 20, 2017. © 2014 American Association for Cancer Research. mcr.aacrjournals. org Downloaded from Published OnlineFirst February 26, 2014; DOI: 10.1158/1541-7786.MCR-13-0545