Association among Vitamin D, Retinoic Acid-Related Orphan Receptors, and Vitamin D Hydroxyderivatives in Ovarian Cancer

Vitamin D and its derivatives, acting via the vitamin D receptor (VDR) and retinoic acid-related orphan receptors gamma and alpha (ROR gamma and ROR alpha), show anticancer properties. Since pathological conditions are characterized by disturbances in the expression of these receptors, in this study, we investigated their expression in ovarian cancers (OCs), as well as explored the phenotypic effects of vitamin D hydroxyderivatives and ROR gamma/alpha agonists on OC cells. The VDR and ROR gamma showed both a nuclear and a cytoplasmic location, and their expression levels were found to be reduced in the primary and metastatic OCs in comparison to normal ovarian epithelium, as well as correlated to the tumor grade. This reduction in VDR and ROR gamma expression correlated with a shorter overall disease-free survival. VDR, ROR gamma, and ROR alpha were also detected in SKOV-3 and OVCAR-3 cell lines with increased expression in the latter line. 20-Hydroxy-lumisterol3 (20(OH)L-3) and synthetic ROR alpha/ROR gamma agonist SR1078 inhibited proliferation only in the OVCAR-3 line, while 20-hydroxyvitamin-D-3 (20(OH)D-3) only inhibited SKOV-3 cell proliferation. 1,25(OH)(2)D-3, 20(OH)L-3, and SR1078, but not 20(OH)D-3, inhibited spheroid formation in SKOV-3 cells. In summary, decreases in VDR, ROR gamma, and ROR alpha expression correlated with an unfavorable outcome for OC, and compounds targeting these receptors had a context-dependent anti-tumor activity in vitro. We conclude that VDR and ROR gamma expression can be used in the diagnosis and prognosis of OC and suggest their ligands as potential candidates for OC therapy.