Prostate cancer growth depends, in its earlier stages, on androgens and is usually pharmacologically modulated with androgen blockade. However, androgen-ablation therapy may generate androgen-independent prostate cancer, often characterized by an increased invasiveness. We have found that the 5A-reduced testosterone derivative, dihydrotestosterone (the most potent natural androgen) inhibits cell migration with an androgen receptor-independent mechanism. We have shown that the dihydrotestosterone metabolite 5A-androstane-3B,17B-diol (3B-Adiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor B (ERB), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERB signaling. Very surprisingly, estradiol is not active, suggesting the existence of different pathways for ERB activation in prostate cancer cells. Moreover, 3B-Adiol, through ERB, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells. The inhibitory effects of 3B-Adiol on prostate cancer cell migration is counteracted by short interfering RNA against E-cadherin. Altogether, the data showed that (a) circulating testosterone may act with estrogenic effects downstream in the catabolic process present in the prostate, and (b) that the estrogenic effect of testosterone derivatives (ERB-dependent) results in the inhibition of cell migration, although it is apparently different from that linked to estradiol on the same receptor and may be protective against prostate cancer invasion and metastasis. These results also shed some light on clinical observations suggesting that alterations in genes coding for 3B-hydroxysteroid dehydrogenases (the enzymes responsible for 3B-Adiol formation) are strongly correlated with hereditary prostate cancer. (Cancer Res 2005; 65(12): 5445-53)

We investigated the presence of glucocorticoid receptors (GR) as well as the role of glucocorticoids (Gc) in the control of proliferation of the androgen-independent prostate cancer cell line, DU145. We detected the presence of a specific high affinity binding site (in the cytosolic preparations of DU145 cells; the density of these binding sites is significantly higher than that detected in HA22T/ VGH and in HepG2, two hepatoma cell lines classically considered models for the study of GR. Immunocytochemistry studies confirmed the presence of GR in the cytosolic compartment of DU145 cells; GR undergo translocation to the nucleus following exposure to dexamethasone (Dex). The functional activity of GR present in DU145 cells was also studied by analyzing the potency of Dex in inducing chloramphenicol acyltransferase (CAT) activity in DU145 cells transfected with a glucocorticoid/progesterone response element (GRE/PRE) tkCAT plasmid (GRE/PREtkCAT plasmid). The results have shown that Dex stimulates the transcriptional activity of GR in transfected DU145 cells with an EC 50 of 9·65 nM and a maximal induction of sevenfold above basal levels. Finally, a dose-dependent (IC 50 3·14 nM) decrease of DU145 cell numbers was observed after their exposure to Dex for 4 days; this effect was counteracted by the presence of the steroid antagonist, RU486. In conclusion, the present data suggest a possible role of corticoids in the control of the growth of androgen-independent prostate cancer.

Prostate cancer (PC) develops as a consequence of abnormal androgenic stimulation. Unfortunately, most of the PC cell lines are androgen independent (like DU145), or express mutated forms of androgen receptor (AR). We have produced and characterized a new stably transfected PC line expressing the AR (DU145-AR). Untreated DU145-AR cells showed a lower proliferation rate than mock transfected cells, but responded to testosterone treatment. PSA mRNA, undetectable in mock DU145 cells, was present and upregulated by testosterone in DU145-AR. About 5% of DU 145-AR cells showed modification of morphology and enriched of f-actin after testosterone treatment. Moreover, in DU145-AR plasminogen activator (PA) activity and secreted urokinase type plasminogen activator (uPA) protein were lower than in AR negative cells; again testosterone induced PA activity and uPA protein only in DU145-AR. These results indicate that, in general, the effects of unactivated AR is to suppress function(s) in DU145 cells and the addition of testosterone restores the normal properties associated with the untransfected cells. Some of the effects described may thus be mediated by a ligand-independent activation of AR in DU145 cells.

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