Numb -/low Enriches a Castration-Resistant Prostate Cancer Cell Subpopulation Associated with Enhanced Notch and Hedgehog Signaling

• Published in: Clinical cancer research Vol. 23; no. 21; pp. 6744 - 6756
• Main Authors: Guo, Yanjing, Zhang, Kai, Cheng, Chaping, Ji, Zhongzhong, Wang, Xue, Wang, Minglei, Chu, Mingliang, Tang, Dean G, Zhu, Helen He, Gao, Wei-Qiang
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.11.2017
• Subjects: Androgens; Androgens - metabolism; Androgens - therapeutic use; Animal tissues; Animals; Apoptosis; Biological effects; Cancer; Castration; Cell Lineage - drug effects; Deprivation; Experimental design; Gene Expression Regulation, Neoplastic; Hedgehog protein; Hedgehog Proteins - genetics; Humans; Immunoblotting; In vivo methods and tests; Male; Membrane Proteins - genetics; Mice; Nerve Tissue Proteins - genetics; NUMB protein; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Notch - genetics; Signal Transduction - genetics; Signaling; Stem cells; Tumor cell lines; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-0913

To elucidate the role and molecular mechanism of Numb in prostate cancer and the functional contribution of Numb prostate cancer cells in castration resistance. The expression of Numb was assessed using multiple datasets and prostate cancer tissues from both humans and mice. The biological effects of the overexpression and knockdown of Numb in human prostate cancer cell lines were investigated and In addition, we developed a reliable approach to distinguish between prostate cancer cell populations with a high or low endogenous expression of Numb protein using a Numb promoter-based lentiviral reporter system. The difference between Numb and Numb prostate cancer cells in the response to androgen-deprivation therapy (ADT) was then tested. The likely downstream factors of Numb were analyzed using luciferase reporter assays, immunoblotting, and quantitative real-time PCR. We show here that Numb was downregulated and negatively correlated with prostate cancer advancement. Functionally, Numb played an inhibitory role in xenograft prostate tumor growth and castration-resistant prostate cancer development by suppressing Notch and Hedgehog signaling. Using a promoter-based lentiviral reporter system, we were able to distinguish Numb prostate cancer cells from Numb cells. Numb prostate cancer cells were smaller and quiescent, preferentially expressed Notch and Hedgehog downstream and stem-cell-associated genes, and associated with a greater resistance to ADT. The inhibition of the Notch and Hedgehog signaling pathways significantly increased apoptosis in Numb cells in response to ADT. Numb enriches a castration-resistant prostate cancer cell subpopulation that is associated with unregulated Notch and Hedgehog signaling. .