Oncotarget

Research Papers:

Progesterone potentiates the growth inhibitory effects of calcitriol in endometrial cancer via suppression of CYP24A1

Amber A. Bokhari, Laura R. Lee, Dewayne Raboteau, Jane Turbov, Isabel V. Rodriguez, John Wesley Pike, Chad A. Hamilton, George Larry Maxwell, Gustavo C. Rodriguez and Viqar Syed _

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Oncotarget. 2016; 7:77576-77590. https://doi.org/10.18632/oncotarget.12725

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Abstract

Amber A. Bokhari1, Laura R. Lee1, Dewayne Raboteau1, Jane Turbov2, Isabel V. Rodriguez2, John Wesley Pike3, Chad A. Hamilton1,4,5, George Larry Maxwell5,6, Gustavo C. Rodriguez2, Viqar Syed1,5,7

1Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

2Division of Gynecologic Oncology, North Shore University Health System, University of Chicago, Evanston, IL, USA

3Department of Biochemistry, University of Wisconsin, Madison, WI, USA

4Division of Gynecologic Oncology, and Gynecologic Cancer Translational Research Center of Excellence, Walter Reed National Military Medical Center, Bethesda, MD, USA

5John P. Murtha Cancer Center at Water Reed National Military Medical Center, Bethesda, MD, USA

6Department of Obstetrics and Gynecology and Women’s Health Integrated Research Center, Inova Fairfax Hospital, Falls Church, VA, USA

7Department of Molecular and Cell Biology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

Correspondence to:

Viqar Syed, email: [email protected]

Keywords: chemoprevention, cell proliferation, progesterone, calcitriol, vitamin D receptor

Received: June 01, 2016    Accepted: October 03, 2016    Published: October 18, 2016

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.


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