Notch‐1 signaling is lost in prostate adenocarcinoma and promotes PTEN gene expression

Abstract

Prostate tumorigenesis is associated with loss of PTEN gene expression. We and others have recently reported that PTEN is regulated by Notch-1 signaling. Herein, we tested the hypothesis that alterations of the Notch-1 signaling pathway are present in human prostate adenocarcinoma and that Notch-1 signaling regulates PTEN gene expression in prostate cells. Prostate adenocarcinoma cases were examined by immunohistochemistry for ligand cleaved (activated) Notch-1 protein. Tumor foci exhibited little cleaved Notch-1 protein, but expression was observed in benign tissue. Both tumor and benign tissue expressed total (uncleaved) Notch-1. Reduced Hey-1 expression was seen in tumor foci but not in benign tissue, confirming loss of Notch-1 signaling in prostate adenocarcinoma. Retroviral expression of constitutively active Notch-1 in human prostate tumor cell lines resulted in increased PTEN gene expression. Incubation of prostate cell lines with the Notch-1 ligand, Delta, resulted in increased PTEN expression indicating that endogenous Notch-1 regulates PTEN gene expression. Chromatin immunoprecipitation demonstrated that CBF-1 was bound to the PTEN promoter. These data collectively indicate that defects in Notch-1 signaling may play a role in human prostate tumor formation in part via a mechanism that involves regulation of the PTEN tumor suppressor gene.

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

“…Upon further examination, microarray analysis revealed that Notch1 and Hey1 genes were significantly down-regulated in prostate adenocarcinoma compared to normal prostate, suggesting that dysregulation of Notch signaling pathway might facilitate prostatic tumorigenesis ). In line with this report, Whelan et al reported loss of total and cleaved Notch1 and Hey1 immunohistochemistry in prostate adenocarcinoma foci (Whelan et al 2009). To further investigate the role of Notch1 signaling in prostate cancer cells, they overexpressed constitutively active Notch1 in the DU145 prostate cancer cell line.…”

“…Moreover, higher Jagged1 expression is significantly associated with recurrence (Santagata et al 2004). However, in the context of cancer etiology, the role of Notch proteins, their ligands and regulation are diverse (Li et al 2007;Shou et al 2001;Wang et al 2006Wang et al , 2010Wang et al , 2011Whelan et al 2009). As reported by Wang et al Notch inactivation might be associated with prostate tumorigenesis .…”

“…Despite Notch expression being up-regulated in prostate cancer and higher with increasing Gleason grade (Santagata et al 2004;Zhu et al 2013), the definitive role of the Notch pathway in human prostate cancer remains unclear. Several studies suggest that Notch signaling inhibits prostate cancer cell proliferation, and loss of Notch1 in prostate adenocarcinoma abolishes its capability to suppress tumor growth (Shou et al 2001;Wang et al 2006;Whelan et al 2009), while others suggest that Notch promotes tumor growth and cancer progression (Li et al 2007;Wang et al 2010Wang et al , 2011. Therefore, Notch's role as a tumor suppressor or an oncogene in prostate adenocarcinoma requires further in-depth investigation to address these controversies.…”

Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells

“…Interestingly, studies have shown that Notch signaling could play an anti-tumor role in prostate cancer. 57,58 Multiple studies suggest Notch is a tumor suppressor in context dependent. 59,60 Therefore, deeper investigation is required to explore the function of Notch-1 using transgenic mouse model in the near future.…”

Tangeretin prevents prostate cancer cell proliferation and induces apoptosis via activation of Notch signalling and regulating the androgen receptor (AR) pathway and the phosphoinositide 3-kinase (PI3k)/Akt/mTOR pathways

“…Furthermore, many studies have reported that Notch 1 signalling regulates PTEN expression in prostate tumors (Palomero et al, 2007;Whelan et al, 2009;Wang et al, 2010).…”