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1.
Oncotarget ; 7(47): 77576-77590, 2016 Nov 22.
Article in English | MEDLINE | ID: mdl-27769055

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.


Subject(s)
Calcitriol/pharmacology , Endometrial Neoplasms/pathology , Progesterone/pharmacology , Vitamin D3 24-Hydroxylase/genetics , Vitamin D3 24-Hydroxylase/metabolism , Adult , Aged , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Synergism , Endometrial Neoplasms/genetics , Endometrial Neoplasms/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Middle Aged , Neoplasm Grading
2.
Cancer Prev Res (Phila) ; 7(10): 1045-55, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25070663

ABSTRACT

Increased expression of TGFß isoforms in human endometrial cancer correlates with decreased survival and poor prognosis. Progesterone has been shown to exert a chemoprotective effect against endometrial cancer, and previous animal models have suggested that these effects are accompanied by changes in TGFß. The goal of this study was to characterize the effect of progesterone on TGFß signaling pathway components and on TGFß-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFß isoforms at 72 hours after treatment except for TGFß2 in HEC-1B and TGFß3 in Ishikawa cells. Progesterone treatment for 120 hours attenuated expression of the three isoforms in all cell lines. Progesterone exposure for 72 hours reduced expression of TGFß receptors in HEC-1B cells and all but TGFßR1 in Ishikawa cells. Progesterone reduced TGFßR3 expression in RL-95 cells at 72 hours, but TGFßR1 and ßR2 expression levels were not affected by progesterone at any time point. SMAD2/3 and pSMAD2/3 were substantially reduced at 72 hours in all cell lines. SMAD4 expression was reduced in RL-95 cells at 24 hours and in HEC-1B and Ishikawa cells at 72 hours following progesterone treatment. Furthermore, progesterone effectively inhibited basal and TGFß1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGFßRI blocked TGFß1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGFß signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth.


Subject(s)
Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/pathology , Progesterone/metabolism , Transforming Growth Factor beta/metabolism , Antigens, CD , Cadherins/metabolism , Cell Line, Tumor , Cell Survival , Culture Media , Culture Media, Conditioned/chemistry , Epithelial-Mesenchymal Transition , Female , Humans , Ligands , Microscopy, Fluorescence , Neoplasm Invasiveness , Signal Transduction , Smad4 Protein/metabolism , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta1/metabolism , Vimentin/metabolism
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