期刊
UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS
卷 27, 期 1, 页码 48-52出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.urolonc.2008.06.002
关键词
Neuroendocrine differentiation; Neuropeptides; Src tyrosine kinase; Androgen receptor activation; Tyrosine kinase inhibitor; Hormone refractory prostate cancers
资金
- NATIONAL CANCER INSTITUTE [R01CA114575] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK052659] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA114575-04S1, R01 CA114575] Funding Source: Medline
- NIDDK NIH HHS [R01 DK052659, R01 DK052659-09] Funding Source: Medline
Background: There is considerable evidence implicating the aberrant activation or reactivation of androgen receptor in the course of androgen-ablation therapy as a potential cause for the development of castration-resistant prostate cancer. Several non-mutually exclusive mechanisms including the inappropriate activation of androgen receptor (AR) by non-steroids have been postulated. The present work is aimed to understand the role of neuropeptides released by neuroendocrine transdifferentiated prostate cancer cells in the aberrant activation of AR. Objectives: The study was designed to study how neuropeptides such as gastrin-releasing peptide activate AR and to define the crucial signal pathways involved, in the hope to identify therapeutic targets. Methods and Materials: Androgen-dependent LNCaP cell line was used to study the effects of bombesin/gastrin-releasing peptide on the growth of the cell line and the transactivation of AR. The neuropeptide was either added to the media or introduced as a transgene in LNCaP cells to study its paracrine or autocrine effect on LNCaP growth under androgen-deprived conditions. The activation of AR was monitored by reporter assay, chromatin immunoprecipitation (ChIP) of AR, translocation into the nucleus and cDNA microarray of the AR response genes. Results: Bombesin/gastrin releasing peptides induce androgen-independent growth of LNCaP in vitro and in vivo. It does so by activating AR, which is accompanied by the activation of Src tyrosine kinase and its target c-myc oncogene. The bombesin or Src-activated AR induces an overlapping set of AR response genes as androgen, but they also a unique set of genes. Intriguingly, the Src-activated and androgen-bound ARs differ in their binding specificity toward AR response elements, indicating the receptors activated by these 2 mechanisms are not conformationally identical. Finally, Src inhibitor was shown to effectively block the activation of AR and the growth effects induced by bombesin. Conclusion: The results showed that AR can be activated by neuropeptide, a ligand for G-protein coupled receptor, in the absence of androgen. The activation goes through Src-tyrosine kinase pathway, and tyrosine kinase inhibitor is a potentially useful adjunctive therapy during androgen ablation. (C) 2009 Elsevier Inc. All rights reserved.
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