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

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Abstract
BACKGROUND RORα 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 RORα are present on the promoter of cell cycle‐related genes suggesting that it might be involved in the control of cell proliferation. In this study, we investigated the expression and the possible function of RORα in a human androgen‐independent prostate cancer cell line (DU 145). The thiazolidinedione‐derivative CGP 52608 has been utilized as the specific ligand and activator of RORα. METHODS The effects of CGP 52608 on DU 145 cell proliferation and cell cycle distribution were analyzed by hemocytometer and by FACS analysis, respectively. The expression of RORα as well as the effects of RORα activation on the expression of cell cycle‐related genes were evaluated by RT‐PCR. To clarify whether RORα activation might affect the proliferation of prostate cancer cells also in vivo, nude mice bearing DU 145 tumor xenografts were treated with CGP 52608 at different doses and the growth of the tumors was followed by caliper measurement. RESULTS RORα is expressed in DU 145 cells and the treatment of the cells with the thiazolidinedione‐derivative CGP 52608 brought about a dose‐dependent and significant decrease of cell proliferation. Ligand‐induced activation of RORα affected cell cycle distribution, inducing an accumulation in the G0/G1 phase and a decrease in the S phase. This effect was accompanied by an increased expression of the cyclin‐dependent kinase inhibitor p21WAF1/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 prostate cancer cells, activation of the orphan nuclear receptor RORα inhibits cell growth, both in vitro and in vivo. RORα also induces cell cycle arrest, possibly through the modulation of the expression of cell cycle‐related genes. Prostate 46:327–335, 2001.