Progestins inhibit calcitriol-induced CYP24A1 and synergistically inhibit ovarian cancer cell viability: An opportunity for chemoprevention.

ABSTRACT

OBJECTIVES: Previously we have shown in endometrial cells that progesterone (P4) and calcitriol (CAL, 1,25(OH)2D3) synergistically promote apoptosis and that progestins induce expression of the vitamin D receptor. In the current study we examined the progestin/vitamin D combination in ovarian cells and searched for other progestin-related effects on vitamin D metabolism that may underlie the novel interaction between progestins and vitamin D, including whether progestins inhibit CYP24A1, the enzyme that renders CAL inactive. METHODS: We investigated the impact of P4 on CAL-induced CYP24A1 expression in cancer cell lines expressing progesterone receptors (PRs), [OVCAR-5, OVCAR-3-PGR (PR-transfected OVCAR-3 ovarian line), and T47D-WT, T47D-A and T47D-B (breast lines expressing PRs or individual PR isoforms)] or lines that do not express PRs (OVCAR-3 and T47D-Y). We examined CYP24A1 expression using RT-PCR and western blotting, and apoptosis by TUNEL. We also investigated P4 inhibition of Cyp24a1 in ovaries from CAL-treated mice. RESULTS: CAL treatment induced CYP24A1 expression. When co-treated with P4, cell lines expressing PRs showed marked inhibition of CYP24A1 expression (p<0.001), along with increased apoptosis (p<0.01); cells not expressing PRs did not. Mouse ovaries showed a significant reduction in CAL-induced Cyp24a1 mRNA (p<0.001) and protein (p<0.01) in response to P4. CONCLUSIONS: We show for the first time that progestins and vitamin D synergistically reduce cell viability and induce apoptosis in ovarian cells and that progestins PR-dependently inhibit CAL-induced CYP24A1, thus extending CAL activity. The combination of progestins and vitamin D deserves further consideration as a strategy for inhibiting ovarian carcinogenesis.