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



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.
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States; Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, United States. Electronic address: grodriguez@northshore.org.
Gustavo C
GC
Rodriguez
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States.
Jane
J
Turbov
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States.
Rebecca
R
Rosales
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States.
Jennifer
J
Yoo
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States; Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, United States.
Jessica
J
Hunn
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States.
Katherine J
KJ
Zappia
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States.
Kaarin
K
Lund
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States.
Catherine P
CP
Barry
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States.
Isabel V
IV
Rodriguez
Department of Biochemistry, University of Wisconsin, Madison, WI, United States.
J Wesley
JW
Pike
Gynecologic Cancer Center of Excellence, Annandale, VA, United States; Inova Schar Cancer Institute, Inova Center for Personalized Health, 3300 Gallows Road, Falls Church, VA, United States.
Thomas P
TP
Conrads
Gynecologic Cancer Center of Excellence, Annandale, VA, United States; Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Inova Medical Campus, Falls Church, VA, United States.
Kathleen M
KM
Darcy
Gynecologic Cancer Center of Excellence, Annandale, VA, United States; Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Falls Church, VA, United States; Department of Obstetrics and Gynecology, Virginia Commonwealth University School of Medicine, Inova Medical Campus, Falls Church, VA, United States.
George Larry
GL
Maxwell
Gynecologic Cancer Center of Excellence, Annandale, VA, United States; Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States; Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, MD, United States.
Chad A
CA
Hamilton
Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States; Department of Molecular and Cell Biology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States.
Viqar
V
Syed
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, IL, United States; Department of Obstetrics and Gynecology, University of Chicago, Chicago, IL, United States.
Larry G
LG
Thaete
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018890:Chemoprevention; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010053:Ovary / Q000201:enzymology; D011374:Progesterone / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000032:analysis / Q000502:physiology; D065668:Vitamin D3 24-Hydroxylase / Q000037:antagonists & inhibitors*
D011980:Receptors, Progesterone; D011374:Progesterone; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol
CYP24A1; Chemoprevention; Ovarian cancer; Progestin; Vitamin D