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

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. © 2001 Wiley‐Liss, Inc.

Activation of the orphan nuclear receptor RORα counteracts the proliferative effect of fatty acids on prostate cancer cells: Crucial role of 5‐lipoxygenase

“…8a). 33 AA stimulated PC3 cell growth, although at a higher dose (5 ϫ 10 Ϫ6 M) than that required to increase DU 145 cell proliferation (Fig. 8b).…”

“…28 We have shown previously that the ROR␣ family is expressed in DU 145 prostate cancer cells. 33 Experiments have now been carried out to identify the specific isoform of the orphan nuclear receptor that might be present in these cells. By RT-PCR, we have observed that only one cDNA band, corresponding to the ROR␣1 cDNA, was present in DU 145 cells (Fig.…”

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

“…RORα has been reported in vitro to affect proliferation and differentiation of DU145 cells (Moretti et al 2001). It also been reported to reduce the invasiveness of prostate cancer cells (Moretti et al 2002).…”

Orphan nuclear receptors as drug targets for the treatment of prostate and breast cancers

“…Prostate [69] RORb RORc Liver X receptor-like (NR1H) LXRa Prostate [87], Breast [190], Colon [191], Pancreas [192], Esophageal [193], Liver [194] …”

“…A number of putative natural and synthetic ligands have been identified that target RORs; most notably cholesterol, cholesterol metabolites and oxysterols that have been shown to bind to the LBD of RORs and induce conformational changes that affect coregulator interactions [66,67]. While recent research has focused on the therapeutic value of inhibiting RORs for treating metabolic and autoimmune diseases, analyses of published gene expression data indicate that RORa is downregulated in multiple cancers including prostate, breast and pancreatic cancer, and suggest that RORa may act as a tumor suppressor [66,[68][69][70].…”