Retracted: Down‐regulation of Jagged‐1 induces cell growth inhibition and S phase arrest in prostate cancer cells

Abstract

Notch is an ancient cell signaling system that regulates cell fate specification, stem cell maintenance and initiation of differentiation in many tissues. It has been reported that Jagged-1, a Notch ligand, is significantly over expressed in metastatic prostate cancer compared to localized prostate cancer or benign prostatic tissues. Therefore, deregulation of Jagged-1 protein levels may play a role in prostate cancer cell growth and progression. Hence, the aim of our current study was to investigate the mechanistic role of Jagged-1 in prostate cancer cell growth and cell cycle progression. Our results show, for the first time, that down-regulation of Jagged-1 induces cell growth inhibition and S phase cell cycle arrest in prostate cancer cells, with reduced CDK2 kinase activity and increased p27 expression. These results suggest that Jagged-1 could be a potential therapeutic target for the treatment of prostate cancer. ' 2006 Wiley-Liss, Inc.

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

“…To examine the potential oncogenic activity of Jagged1 and to uncover its coregulators or downstream targets at the molecular level, we measured prostate cancer cell proliferation and the cell cycle affected by knockdown or overexpression of Jagged1. Consistent with previous results (19,28), we found that downregulation of Jagged1 significantly inhibited cell proliferation with a similar activity in all tested prostate cancer cell lines, including LNCaP, LAPC4, DU145, and PC3, and inhibited the cell cycle at S phase, which is direct evidence that Each experiment was performed in triplicate, and data represent the mean AE SD. B, luciferase reporter assays were performed in LNCaP cells with three constructs [empty pGL-3 basic vector (negative control), vector with two copies of ARE elements (positive control), and vector with the promoter region of cyclin B1] with or without MK-2206.…”

“…Expression level of Jag1 has a positive correlation with the progression of prostate cancer Jagged1 and its coding gene, Jag1, were shown, in many studies, to have a closed correlation with prostate cancer (23)(24)(25)(26)(27)(28), which suggests that Jagged1 functions to promote prostate cancer development. Therefore, we further analyzed Jag1 expressions in prostate cancer tissue samples and normal prostate tissue samples to examine whether Jag1 has a significant higher expression level in advanced prostate cancer.…”

“…Moreover, a positive correlation between Jagged1 and prostate-specific antigen (PSA) recurrence after radical prostatectomy has been found (17), which suggests that high jagged1 protein expression is a strong predictor of prostate cancer recurrence. In addition, synthetic androgen R1881 can enhance Jagged1 expression in LNCaP cells, and knockdown of Jagged1 expression would inhibit LNCaP cell proliferation (25,28), suggesting that Jagged1-mediated Notch activation of LNCaP cells plays an oncogenic role in promoting cell proliferation. Downregulation of Jagged1 has been shown to have the same property in the other prostate cancer cell lines, DU145 and PC3, through a mechanism that regulates CDK2 and p27 activities (19,28).…”

“…In addition, synthetic androgen R1881 can enhance Jagged1 expression in LNCaP cells, and knockdown of Jagged1 expression would inhibit LNCaP cell proliferation (25,28), suggesting that Jagged1-mediated Notch activation of LNCaP cells plays an oncogenic role in promoting cell proliferation. Downregulation of Jagged1 has been shown to have the same property in the other prostate cancer cell lines, DU145 and PC3, through a mechanism that regulates CDK2 and p27 activities (19,28). Therefore, growth inhibition of prostate cancer cells by downregulated Jagged1 indicates that Jagged1 could be an important target in the Notch signaling pathway for the treatment of prostate cancer.…”

siRNA-mediated Silencing of Notch-1 Enhances Docetaxel Induced Mitotic Arrest and Apoptosis in PCa Cells

“…Furthermore, down-regulation of Notch-1 led to a marked arrest in cell cycle progression after 24 h, as characterized by the loss of cells in the G 1 phase and an accumulation of cells in the S phase ( Figure 2C). This is in agreement with the reported cell cycle arrest induced by Notch-1 siRNA (Zhang et al, 2006). Notably, compared to docetaxel treatment, the combination treatment with Notch-1 siRNA and docetaxel induced a significant increase in G 2 /M arrest ( Figure 2E), suggesting a synergistic effect of Notch-1 depletion and docetaxel in inducing cell cycle arrest.…”