Gonadotropin-releasing hormone functionally antagonizes testosterone activation of the human androgen receptor in prostate cells through focal adhesion complexes involving Hic-5.
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 the inhibition of gonadotropins and resultant decrease in androgen. However, GnRH analogs have also been shown to directly inhibit prostate cancer cells both in vitro and in vivo through antiproliferative cell cycle arrest and stimulation of apoptosis. Since the GnRH receptor has been shown to affect sex steroid hormone receptor function, we considered that part of GnRH analog actions on prostate cells may be mediated through modulation of the human androgen receptor. Using a model HEK293 cell line expressing the GnRH receptor, we demonstrated a novel signalling pathway of the GnRH receptor that induces nuclear translocation of the androgen receptor that renders it transcriptionally inactive. This mechanism involves the calcium-dependent tyrosine kinase Pyk2, the non-receptor tyrosine kinase c-Src and the focal adhesion protein/steroid receptor co-factor, Hic-5. In this setting there is a GnRH-induced association and nuclear translocation of the androgen receptor with Hic-5. GnRH-induced Pyk2 activation opposed the association of Hic-5 with androgen receptor as overexpression of a dominant negative Pyk2 enhanced the GnRH-induced nuclear translocation of a green fluorescent protein-tagged human androgen receptor. GnRH-induced c-Src activation resulted in the phosphorylation of expressed Hic-5 and promoted its association with the human androgen receptor. In contrast to testosterone, GnRH-induced nuclear translocation did not transcriptionally activate the androgen receptor. We then demonstrated that GnRH can also stimulate androgen receptor mobilization in human prostate PC3, BPH-1 and LNCaP cells, and in cultured rat ventral prostate cells through the same mechanism. To determine if GnRH could antagonize androgen effects in normal tissue, we examined the effect of GnRH on rat ventral prostate organ cultures and demonstrated that GnRH can functionally antagonize the actions of testosterone on prostate cell proliferation and tissue growth. This antagonism of testosterone action by GnRH may underlie in part the capacity of GnRH receptor activation to inhibit prostate tumor growth.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T31 T32 T33 T34 T35 T36 T37 T38 T39 T3 T40 T41 T42 T43 T44 T45 T46 T47 T48 T49 T4 T50 T51 T52 T53 T54 T55 T56 T57 T58 T59 T5 T60 T61 T62 T63 T64 T65 T66 T67 T68 T69 T6 T7 T8 T9
CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-Y GENE-N GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL GENE-Y GENE-Y GENE-N GENE-Y GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL
GnRH GnRH testosterone testosterone GnRH GnRH GnRH GnRH GnRH GnRH Gonadotropin-releasing hormone GnRH GnRH calcium tyrosine tyrosine Gonadotropin-releasing hormone testosterone Gonadotropin-releasing hormone steroid receptor co-factor Hic-5 GnRH GnRH androgen receptor Hic-5 GnRH Pyk2 Hic-5 androgen receptor Pyk2 GnRH human androgen receptor GnRH GnRH c-Src Hic-5 human androgen receptor GnRH androgen receptor GnRH androgen receptor GnRH GnRH GnRH GnRH GnRH GnRH receptor GnRH GnRH GnRH receptor sex steroid hormone receptor GnRH human androgen receptor GnRH receptor GnRH GnRH receptor androgen receptor tyrosine kinase Pyk2 non-receptor tyrosine kinase c-Src focal adhesion protein Gonadotropin-releasing hormone Hic-5 human androgen receptor testosterone GnRH GnRH GnRH