Abstract
Abstract Human studies suggest that progesterone and calcitriol may prove beneficial in preventing or inhibiting oncogenesis, but the underlying mechanism is not fully understood. The current study investigates the effects of progesterone, calcitriol and their combination on immortalized human endometrial epithelial cells and endometrial cancer cells and identifies their targets of action. The combined cell treatment enhanced vitamin D receptor expression and synergistically inhibited cell proliferation through caspase-3 activation and induction of G0/G1 cell cycle arrest with associated down-regulation of cyclin D1, D3 and p27 induction. We used mass spectrometry-based proteomics to measure protein abundance differences between calcitriol-, progesterone-, or combination-exposed endometrial cells. A total of 117 proteins showed differential expression amongst these three treatments. Four proteins were then selected for validation studies: histone H1.4 (HIST1H1E), histidine triad nucleotide-binding protein 2 (HINT2), interferon-induced, double-stranded RNA-activated protein kinase (EIF2AK2), and Bcl-2-associated X protein (BAX). Abundance levels of selected candidates were low in endometrial cancer cell lines versus the immortalized endometrial epithelial cell line. All four proteins displayed elevated expression in cancer cells upon exposure to calcitriol, progesterone or the combination. Further BAX analysis through gain or loss of function experiments revealed that upregulation of BAX decreased cell proliferation by changing the BAX:Bcl2 ratio. Knock down of BAX attenuated progesterone- and calcitriol-induced cell growth inhibition. Our results showed that progesterone and calcitriol up-regulate the expression of BAX along with other apoptosis-related proteins, which induced inhibition of endometrial cancer cell growth by apoptosis and cell cycle arrest. Citation Format: Laura R. Lee, Brian L. Hood, Huyen Nguyen, Leyla Kavandi, Jane M. Turbov, Larry G. Thaete, Chad A. Hamilton, Gustavo C. Rodriguez, George L. Maxwell, Thomas P. Conrads, Viqar Syed. Calcitriol and progesterone synergistically inhibit growth in endometrial cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1716. doi:10.1158/1538-7445.AM2013-1716
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