Oncogenic activation of androgen receptor.
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.


OBJECTIVE
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
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.


CONCLUSIONS
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.
Kung
Hsing-Jien
HJ
Department of Basic Sciences, University of California, Davis Cancer Center, Sacramento, CA 95817, USA. hkung@ucdavis.edu
Evans
Christopher P
CP
D045744:Cell Line, Tumor; D019886:Gastrin-Releasing Peptide / Q000737:chemistry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008297:Male; D008954:Models, Biological; D009479:Neuropeptides / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D011944:Receptors, Androgen / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D008024:Ligands; D009479:Neuropeptides; D010455:Peptides; D011944:Receptors, Androgen; D013256:Steroids; D019886:Gastrin-Releasing Peptide; D019061:src-Family Kinases