Gonadotropin-releasing hormone functionally antagonizes testosterone activation of the human androgen receptor in prostate cells through focal adhesion complexes involving Hic-5.

摘要: Gonadotropin-releasing hormone (GnRH) analogs constitute the most widely employed medical treatment for prostatic cancer. The predominant mechanism of action is presumed to be via inhibition gonadotropins and resultant decrease in androgen. However, GnRH have also been shown directly inhibit prostate cancer cells both vitro vivo through antiproliferative cell cycle arrest stimulation apoptosis. Since receptor has affect sex steroid function, we considered that part analog actions on may mediated modulation human androgen receptor. Using a model HEK293 line expressing receptor, demonstrated novel signalling pathway induces nuclear translocation renders it transcriptionally inactive. This involves calcium-dependent tyrosine kinase Pyk2, non-receptor c-Src focal adhesion protein/steroid co-factor, Hic-5. In this setting there GnRH-induced association with Pyk2 activation opposed Hic-5 as overexpression dominant negative enhanced green fluorescent protein-tagged resulted phosphorylation expressed promoted its contrast testosterone, did not activate We then can stimulate mobilization PC3, BPH-1 LNCaP cells, cultured rat ventral same mechanism. To determine if could antagonize effects normal tissue, examined effect organ cultures functionally testosterone proliferation tissue growth. antagonism by underlie capacity tumor