Dr. Kung discussed AR activation via mutation and AR activation by neuropeptides. The cell line CWR22 is androgen independent and after castration 35% will demonstrate AI relapse. A subtype CWR22Rv1 is AI, but androgen responsive. The mechanism responsible for this was investigated. A duplication mutation in AR axon 3 results in protein cleavage and is constitutively activated, which was reversible when the wild type AR was transfected back into the cell. Calpain is the enzyme that is responsible for the cleavage to yield the truncated molecule. A Calpain inhibitor blocked this.
Regarding nonsteroidal activation of AR by neuropeptides, androgen-deprivation in cell lines results in neuroendocrine differentiation and AI growth. These cells are post-mitotic, apoptosis resistant, express neuronal markers and release neurokines. Neuropeptides exogenously administered to LNCaP cells resulted in AI growth. Neuropeptide expressing LNCaP cells grown in castrated mice demonstrate nuclear translocation. AR responsive genes (about half) are induced in this model as demonstrated by AR chromatin immunoprecipitation assay (ChIP) on chip assay. The neuropeptide bombesin recruits AR to the proximal ARE promoter site, but not the enhancer site. This suggests that the activation of AR has different conformation with neuropeptide activation compared with DHT activation. A tyrosine kinase complex of Src, FAK and Etk are the mediators of the neuropeptide mediated activation of AR. The Src kinase inhibitor PP2 blocks the AI growth and migration of neuropeptide tumors. AR phosphorylation may be direct or indirect by Src. This paradigm applies to IL-6, IL-8 and other growth factors. This research provides significant insight into growth factor and neurokine mediated activation of AR.
From the SUO/SBUR Joint Meeting - Saturday, May 19, 2007 - AUA Annual Meeting, Anaheim, CA
Reported by UroToday Contributing Editor Christopher P. Evans, MD, FACS
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