RESUMO
In vitro models of normal and malignant human prostate are currently limited to a few well established cell lines that, with a single exception (LNCaP), fail to express the androgen receptor (AR) - a common characteristic of prostatic epithelium grown in culture. To investigate the molecular mechanism of action of the non-steroidal antiandrogen Casodex (bicalutamide) against wild-type AR, we have established a transient AR expression model in non-tumorigenic prostate cells of both epithelial and mesenchymal origin. In this model, both dihydrotestosterone and Casodex can effectively transport the AR protein into the nucleus of prostate cells. Whereas the natural ligand, dihydrotestosterone, stabilises the receptor, the AR is rapidly degraded at a nuclear location when the transfected cells are treated with Casodex. In contrast, whereas the mutant AR in the LNCaP line is also degraded on Casodex treatment over the same time period, its intracellular targeting is defective.
Assuntos
Antagonistas de Androgênios/farmacologia , Anilidas/farmacologia , Próstata/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Apoptose , Northern Blotting , Western Blotting , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Imunofluorescência , Vetores Genéticos , Humanos , Masculino , Nitrilas , Próstata/citologia , Próstata/metabolismo , Receptores Androgênicos/genética , Compostos de Tosil , TransfecçãoRESUMO
The androgen receptor pathway is known to be a key regulator of growth in the normal and pathological prostate. However, the precise mechanisms of this signaling pathway with respect to the different cellular compartments of the prostate remain largely unknown. We have used a primary culture system to grow human prostatic epithelial cells of normal, benign, tumor and metastatic origin, as well as immortalized human prostatic epithelial cell lines, to demonstrate the absence of a direct or indirect effect of androgens on cellular proliferation in vitro. In parallel to this observed androgen independence for growth, all cell systems lost significant expression of androgen receptor, prostate-specific antigen and prostatic acid phosphatase. Since the androgen receptor is expressed in the epithelium in situ, our results suggest that the androgen effect on epithelial cells may be one of prostatic differentiation rather than proliferation, and that the androgen receptor/growth factor pathway acts through mesenchymal-epithelial interactions.