Progestins inhibit calcitriol-induced CYP24A1 and synergistically inhibit ovarian cancer cell viability: An opportunity for chemoprevention
| Autor: | Jennifer Yoo, J. Wesley Pike, Kathleen M. Darcy, Katherine J. Zappia, Chad A. Hamilton, Gustavo C. Rodriguez, George L. Maxwell, Kaarin Lund, Jane Turbov, Catherine P. Barry, R. Rosales, Thomas P. Conrads, Viqar Syed, Jessica Hunn, Isabel V. Rodriguez, Larry G. Thaete |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Calcitriol Cell Survival Vitamin D3 24-Hydroxylase Biology Chemoprevention Calcitriol receptor Mice 03 medical and health sciences 0302 clinical medicine CYP24A1 Cell Line Tumor Internal medicine polycyclic compounds medicine Vitamin D and neurology Animals Humans Viability assay skin and connective tissue diseases Progesterone Ovarian Neoplasms Ovary Obstetrics and Gynecology Drug Synergism medicine.disease Mice Inbred C57BL 030104 developmental biology Endocrinology Oncology Apoptosis 030220 oncology & carcinogenesis Cancer research Female Receptors Progesterone Ovarian cancer hormones hormone substitutes and hormone antagonists medicine.drug |
| Zdroj: | Gynecologic Oncology. 143:159-167 |
| ISSN: | 0090-8258 |
| DOI: | 10.1016/j.ygyno.2016.04.022 |
| Popis: | 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.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.CAL treatment induced CYP24A1 expression. When co-treated with P4, cell lines expressing PRs showed marked inhibition of CYP24A1 expression (p0.001), along with increased apoptosis (p0.01); cells not expressing PRs did not. Mouse ovaries showed a significant reduction in CAL-induced Cyp24a1 mRNA (p0.001) and protein (p0.01) in response to P4.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. |
| Databáze: | OpenAIRE |
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