Abstract
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 detailed molecular mechanism of 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. This study could benefit our clinical treatments for patients with prostate cancer with overexpressed Jagged1 by targeting AR and Akt.
Highlights
Prostate cancer is one of the most commonly diagnosed noncutaneous cancers and a leading cause of cancer-related deaths in American men [1]
Jag1 expression levels were examined in a total of 218 tissue samples from the Xinhua Hospital, Shanghai, China, which included 130 primary prostate cancer samples, 51 prostate cancer metastasis samples, and 37 matched normal prostate samples (34 normal prostate samples matched to primary prostate cancer samples and three normal prostate samples matched to the metastasis samples; Fig. 1)
We investigated the oncogenic activities of Jagged1 with different expression levels and found that Jagged1 can increase prostate cancer cell proliferation rates and regulate the cell cycle
Summary
Prostate cancer is one of the most commonly diagnosed noncutaneous cancers and a leading cause of cancer-related deaths in American men [1]. 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 in many prostate cancer cells and has been proved to play a significant role in the tumorigenesis and metastasis of prostate cancer [3, 4]. Inhibiting the activities of AR is an important direction in the treatment of primary prostate cancer to prevent tumor
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