Androgen receptor signaling and vitamin D receptor action in prostate cancer cells.

1,25(OH)2D3 inhibits the growth of prostate cancer cells; previous reports suggest that 1,25(OH)2D3 actions in LNCaP prostate cancer cells are androgen dependent. This is due in part to the observation that the androgen receptor (AR) antagonist, Casodex, modestly inhibits LNCaP cell growth, but reduces the greater growth inhibition induced by 1,25(OH)2D3 to the level of Casodex alone. Because androgen ablation therapy is used for metastatic prostate cancer, we sought to better characterize this androgen dependence. We have assessed the requirement for endogenous androgens in 1,25(OH)2D3 mediated growth inhibition of AR+ prostate cancer cell lines. We have also sought the mechanism for anti-androgen mediated reversal of 1,25(OH)2D3 dependent growth inhibition in LNCaP cells. Although 1,25(OH)2D3 does not inhibit the growth of LNCaP cells grown in medium lacking androgens, we find that growth of androgen independent derivatives of LNCaP cells is inhibited by 1,25(OH)2D3. Despite this independence, Casodex treatment reduced the response of these cells to 1,25(OH)2D3 suggesting a unique function for Casodex-bound AR. Because Casodex does not directly inhibit the transcriptional activity of the vitamin D receptor (VDR) we sought a common primary target of VDR and AR action whose VDR dependent transcription could be repressed by Casodex. We report that AS3 (APRIN), a novel gene required for androgen dependent growth arrest, is a primary target for 1,25(OH)2D3 and androgens. Moreover, Casodex reduces induction of AS3 by 1,25(OH)2D3 suggesting that it is a candidate for the Casodex effect. Analysis of functional interactions between AR and VDR in other AR containing prostate cancer cells lines (PC-3 AR, LAPC-4, and 22Rv1) revealed that Casodex reversal was unique to LNCaP derived cells. Anti-androgen mediated reversal of 1,25(OH)2D3 dependent growth inhibition is limited to LNCaP derived prostate cancer cell lines. Moreover, the growth of androgen independent derivatives of LNCaP cells in medium depleted of androgens is strongly inhibited by 1,25D. Therefore, most forms of androgen ablation should not eliminate the utility of VDR agonist treatment in most prostate cancers.

Murthy S ，Agoulnik IU ，Weigel NL 《PROSTATE》

Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence.

Unni E ，Sun S ，Nan B ，McPhaul MJ ，Cheskis B ，Mancini MA ，Marcelli M ... -  《CANCER RESEARCH》

1alpha,25-dihydroxyvitamin D3 inhibits prostate cancer cell growth by androgen-dependent and androgen-independent mechanisms.

Zhao XY ，Peehl DM ，Navone NM ，Feldman D ... -  《ENDOCRINOLOGY》

1alpha,25-dihydroxyvitamin D3 actions in LNCaP human prostate cancer cells are androgen-dependent.

Zhao XY ，Ly LH ，Peehl DM ，Feldman D ... -  《ENDOCRINOLOGY》

Hormonal regulation of beta2-adrenergic receptor level in prostate cancer.

Androgen deprivation is the only effective systemic therapy available for patients with prostatic carcinoma, but is associated with a gradual transition to a hormone-refractory prostate cancer (HRCAP) in which ligand-independent activation of the androgen receptor has been implicated. The beta(2)-adrenergic receptor (beta(2)-AR) is a well-known activator of the androgen receptor. Prostatic cell lines were analyzed using cDNA micro-array, real time RT-PCR, radioligand binding assay, cAMP measurements, transfection and thymidine incorporation assay. Clinical specimens were studied by immunohistochemistry and Affymetrix microarrays. Here, we show that beta(2)-AR was transiently down-regulated both at mRNA- and protein levels when hormone-sensitive prostate cancer cells, LNCaP, were cultured in steroid stripped medium (charcoal-stripped fetal calf serum) or when the cells were treated with the anti-androgen, bicalutamide (Casodex). The number of beta-adrenergic receptors was modestly up-regulated in androgen independent cell lines (LNCaP-C4, LNCaP-C4-2 and DU145) compared to LNCaP. Triiodothyronine (T3) increased the level of beta(2)-AR and the effect of T3 was inhibited by bicalutamide. Immunohistochemical staining of human prostate specimens showed high expression of beta(2)-AR in glandular, epithelial cells and increased expression in malignant cells compared to benign hyperplasia and normal tissue. Interestingly, beta(2)-AR mRNA was strongly down-regulated by androgen ablation therapy of prostate cancer patients. The level of beta(2)-AR was increased by T3 in prostatic adenocarcinoma cells and reduced in prostate cancer patients who had received androgen ablation therapy for 3 months.

Ramberg H ，Eide T ，Krobert KA ，Levy FO ，Dizeyi N ，Bjartell AS ，Abrahamsson PA ，Taskén KA ... -  《PROSTATE》