Activation of the orphan nuclear receptor ROR alpha induces growth arrest in androgen-independent DU 145 prostate cancer cells

BACKGROUND. ROR alpha is a transcription factor which belongs to the family of orphan nuclear receptors. The regulatory functions of this receptor are still poorly understood. However, response elements for ROR alpha are pres ent on the promoter of cell cycle-related genes suggesting that it might be involved in the control of cell proliferation. In this study, we investiga ted the expression and the possible function of ROR alpha in a human androg en-independent prostate cancer cell line (DU 145). The thiazolidinedione-de rivative CGP 52608 has been utilized as the specific ligand and activator o f RORa. METHODS. The effects of CGP 52608 on DU 145 cell proliferation and cell, cy cle distribution were analyzed by hemocytometer and by FAGS analysis, respe ctively The expression of ROR alpha as well as the effects of ROR alpha act ivation on the expression of cell cycle-related genes were evaluated by RT- PCR. To clarify whether ROR alpha activation might affect the proliferation of prostate cancer cells also in vivo, nude mice bearing DU 145 tumor xeno grafts were treated with CGP 52608 at different doses and the growth of the tumors was followed by caliper measurement. RESULTS. RORa is expressed in DU 145 cells and the treatment of the cells w ith the thiazolidinedione-derivative CGP 52608 brought about a dose-depende nt and significant decrease of cell proliferation. Ligand-induced activatio n of ROR alpha affected cell cycle distribution, inducing an accumulation i n the G(0)/G(1) phase and a decrease in the S phase. This effect was accomp anied by an increased expression of the cyclin-dependent kinase inhibitor p 21(WAF1/CIP1) and a decreased expression of cyclin A. The growth of DU 145 tumors in nude mice was significantly reduced by treatment with CGP 52608. CONCLUSIONS. These data indicate that, in androgen-independent DU 145 prost ate cancer cells, activation of the orphan nuclear receptor RORa inhibits c ell growth, both in vitro and in vivo. RORa also induces cell cycle arrest, possibly through the modulation of the expression of cell cycle-related ge nes. Prostate 46:327-335, 2001. (C) 2001 Wiley-Liss, Inc.