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Notch-4 silencing inhibits prostate cancer growth and EMT via the NF-κB pathway
Jianwei Zhang1, Youlin Kuang2, Yan Wang3
1Department of Urology Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. jianweizhanghn@163.com.
Abstract:
Epithelial-mesenchymal transition (EMT) is implicated in the metastasis of human prostate cancer (PCa). Notch signaling has been established as a regulator of EMT. Notch-4 has emerged as a mammary proto-oncogene and a target in several cancers. However, the role and the mechanism of action of Notch-4 in PCa are still unclear. In the present study, we first observed a marked increase in Notch-4 expression in the PCa cell lines DU145, PC3 and LnCAP compared with the non-malignant prostate epithelial cell line RWPE1. Knocking down the expression of Notch-4 suppressed the viability and proliferation in the PCa cell lines DU145 and PC3. Also, further study showed that a decline in Notch-4 significantly promoted apoptosis in PC3 cells. Notch-4 silencing also resulted in decreased cell migration and invasion and affected the expression of EMT markers. We hypothesized that Notch-4 ablation suppresses the activity of NF-κB, so we used PMA to stimulate NF-κB p50 and p65 activation in PC3 cells. The results indicate that PMA treatment impaired the action of Notch-4 ablation in the biology of PC3 cells including cell growth, apoptosis, migration, invasion and EMT. The results of the present study show that RNAi targeting against Notch-4 expression suppresses PCa progression.
Insights
Targeting Notch-4 with RNA interference suppresses prostate cancer (PCa) progression by inhibiting cell viability, proliferation, migration, and invasion, while promoting apoptosis. This suggests Notch-4 is a key driver in PCa metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Epithelial-mesenchymal transition (EMT) drives prostate cancer (PCa) metastasis.
- Notch signaling regulates EMT, with Notch-4 implicated in various cancers.
- The specific role of Notch-4 in PCa progression remains unclear.
Purpose of the Study:
- To investigate the role and mechanism of Notch-4 in human prostate cancer.
- To determine if targeting Notch-4 can inhibit PCa progression.
Main Methods:
- Assessed Notch-4 expression in PCa cell lines (DU145, PC3, LnCAP) versus normal cells (RWPE1).
- Utilized RNA interference (RNAi) to knock down Notch-4 expression.
- Evaluated effects of Notch-4 silencing on cell viability, proliferation, apoptosis, migration, invasion, and EMT markers.
- Investigated the involvement of NF-κB signaling pathway using PMA stimulation.
Main Results:
- Notch-4 expression was significantly elevated in PCa cell lines.
- Notch-4 knockdown suppressed PCa cell viability, proliferation, migration, and invasion.
- Notch-4 silencing promoted apoptosis in PC3 cells and affected EMT markers.
- NF-κB activation via PMA partially reversed the effects of Notch-4 ablation.
Conclusions:
- Notch-4 plays a crucial role in promoting prostate cancer progression and metastasis.
- RNAi targeting Notch-4 effectively suppresses PCa growth and spread.
- Notch-4 may exert its effects partly through the NF-κB signaling pathway.