title: Progesterone potentiates the growth inhibitory effects of calcitriol in endometrial cancer via suppression of CYP24A1.
abstract: Here, we evaluated the expression of CYP24A1, a protein that inactivates vitamin D in tissues. CYP24A1 expression was increased in advanced-stage endometrial tumors compared to normal tissues. Similarly, endometrial cancer cells expressed higher levels of CYP24A1 than immortalized endometrial epithelial cells. RT-PCR and Western blotting were used to examine CYP24A1 mRNA and protein levels in endometrial cancer cells after 8, 24, 72, and 120 h of exposure to progesterone, progestin derivatives and calcitriol, either alone or in combination. Progestins inhibited calcitriol-induced expression of CYP24A1 and splice variant CYP24SV mRNA and protein in cancer cells. Furthermore, actinomycin D, but not cycloheximide, blocked calcitriol-induced CYP24A1 splicing. siRNA-induced knockdown of CYP24A1 expression sensitized endometrial cancer cells to calcitriol-induced growth inhibition. These data suggest that CYP24A1 overexpression reduces the antitumor effects of calcitriol in cancer cells and that progestins may be beneficial for maintaining calcitriol's anti-endometrial cancer activity.
authors: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors: Amber A
authors: AA
authors: Bokhari
authors: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors: Laura R
authors: LR
authors: Lee
authors: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors: Dewayne
authors: D
authors: Raboteau
authors: Division of Gynecologic Oncology, North Shore University Health System, University of Chicago, Evanston, IL, USA.
authors: Jane
authors: J
authors: Turbov
authors: Division of Gynecologic Oncology, North Shore University Health System, University of Chicago, Evanston, IL, USA.
authors: Isabel V
authors: IV
authors: Rodriguez
authors: Department of Biochemistry, University of Wisconsin, Madison, WI, USA.
authors: John Wesley
authors: JW
authors: Pike
authors: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.|Division of Gynecologic Oncology, and Gynecologic Cancer Translational Research Center of Excellence, Walter Reed National Military Medical Center, Bethesda, MD, USA.|John P. Murtha Cancer Center at Water Reed National Military Medical Center, Bethesda, MD, USA.
authors: Chad A
authors: CA
authors: Hamilton
authors: John P. Murtha Cancer Center at Water Reed National Military Medical Center, Bethesda, MD, USA.|Department of Obstetrics and Gynecology and Women's Health Integrated Research Center, Inova Fairfax Hospital, Falls Church, VA, USA.
authors: George Larry
authors: GL
authors: Maxwell
authors: Division of Gynecologic Oncology, North Shore University Health System, University of Chicago, Evanston, IL, USA.
authors: Gustavo C
authors: GC
authors: Rodriguez
authors: Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.|John P. Murtha Cancer Center at Water Reed National Military Medical Center, Bethesda, MD, USA.|Department of Molecular and Cell Biology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors: Viqar
authors: V
authors: Syed
mesh_terms: D000328:Adult; D000368:Aged; D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D011374:Progesterone / Q000494:pharmacology*; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics* / Q000378:metabolism*
chemical_list: D011374:Progesterone; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol
keywords: calcitriol; cell proliferation; chemoprevention; progesterone; vitamin D receptor