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》

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》

Antagonistic interaction between bicalutamide (Casodex) and radiation in androgen-positive prostate cancer LNCaP cells.

Bicalutamide (Casodex) reportedly improves high-risk prostate cancer survival as an adjuvant treatment following radiotherapy. However, biological data for the interaction between bicalutamide and ionizing radiation in concomitant association are lacking. To explore this issue, androgen-dependent (LNCaP) and -independent (DU145) human prostate cancer cells were exposed for 48 hr to 20, 40, or 80 microM bicalutamide introduced before (neoadjuvant), during (concomitant), or following (adjuvant) radiation. Growth inhibition and cytotoxicity, cell cycle distribution and expression of the prostate serum antigen (PSA) and androgen receptor (AR), were measured as endpoints. Bicalutamide-induced cytotoxic and cytostatic effects were found to be correlated with a marked G1 phase arrest and S phase depression. The drug down-regulated PSA and AR proteins and psa mRNA in LNCaP cells. However, transient up-regulation of the expression of ar mRNA was observed in the presence of 40 microM drug. DU145 cells did not express PSA and proved to be comparatively resistant to the drug from both cytostatic and cytotoxic effects. Bicalutamide dose-dependently induced a significant decrease of radiation susceptibility among drug survivors in LNCaP cells, whilst the interaction appeared to be additive in DU145 cells. The antagonistic radiation-drug interaction observed in LNCaP cells is of significance in relation to combined radiotherapy-bicalutamide treatments directed against tumors expressing the AR. The results suggest that bicalutamide is amenable to combined schedule with radiotherapy provided the drug and radiation are not given in close temporal proximity.

Quéro L ，Giocanti N ，Hennequin C ，Favaudon V ... -  《-》

Androgen sensitivity related proteins in hormone-sensitive and hormone-insensitive prostate cancer cell lines treated by androgen antagonist bicalutamide.

Madarová J ，Lukesová M ，Hlobilková A ，Riháková P ，Murray PG ，Student V ，Vojtsek B ，Kolár Z ... -  《NEOPLASMA》

Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system.

Culig Z ，Hoffmann J ，Erdel M ，Eder IE ，Hobisch A ，Hittmair A ，Bartsch G ，Utermann G ，Schneider MR ，Parczyk K ，Klocker H ... -  《-》