Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged1 in Prostate Cancer by Enhancing Cyclin B1 Expression via Akt Phosphorylation

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.

The bHLH Transcription Factor NeuroD Governs Photoreceptor Genesis and Regeneration Through Delta-Notch Signaling

“…[86][87][88][89] Notch signaling also indirectly regulates cyclinB1 expression. 90 Therefore, transcriptional repression of Notch signaling by NeuroD provides a mechanistic link between NeuroD and cell cycle regulation through cyclinB1 and cyclinD1 (see also the report by Ochocinska and Hitchcock 7 ). Earlier work determined that NeuroD governs photoreceptor genesis and maturation in the developing zebrafish retina.…”

Notch signaling in the prostate: critical roles during development and in the hallmarks of prostate cancer biology

“…In prostate cancer cell lines, such as DU145, LNCaP and PC3, Notch1 is expressed at various levels (Shou et al 2001). In human prostate samples, among 218 prostate cancer samples examined, Jagged1 mRNA expression levels were significantly higher in primary tumor and metastasis samples compared to normal samples (Yu et al 2014). Likewise, Zhu et al reported that Jagged1 and Notch1 protein levels were elevated in advanced prostate cancers (Zhu et al 2013).…”

“…It was shown that AR-negative prostate cancer cell lines, DU145 and PC3, when overexpressed with AR and Jagged1, significantly increased their proliferation rates to a level similar to that of an AR-positive prostate cancer cell line, LNCaP, which overexpressed Jagged1 (Yu et al 2014). They reported that AR together with Jagged1 increased the phosphorylation of Akt and the expression level of cyclin B1, promoting prostate cancer cell growth.…”

“…A recent report showed that AR promoted the oncogenic property of Jagged1, a Notch ligand whose overexpression is associated with prostate cancer progression, in prostate cancer cell lines (Yu et al 2014). It was shown that AR-negative prostate cancer cell lines, DU145 and PC3, when overexpressed with AR and Jagged1, significantly increased their proliferation rates to a level similar to that of an AR-positive prostate cancer cell line, LNCaP, which overexpressed Jagged1 (Yu et al 2014).…”

“…They reported that AR together with Jagged1 increased the phosphorylation of Akt and the expression level of cyclin B1, promoting prostate cancer cell growth. Furthermore, high expression of AR and Jagged1 predicted a worse prognosis in prostate cancer patients (Yu et al 2014).…”