Abstract 37: Role and regulation of CYP24A1 in endometrial cancer

The cytochrome P450 enzyme, 24-hydroxylase, encoded by CYP24A1 is critical for the catabolism of 1,25(OH)2D3 (calcitriol). The unbalanced high levels of CYP24A1 seem to be a determinant of calcitriol resistance in tumors. We have previously shown that progesterone enhances calcitriol antitumor activity by upregulating vitamin D receptor expression and promoting apoptosis in endometrial cancer cells. In the present study, we evaluated CYP24A1 protein expression in normal and endometrial tumor tissues, assessed the effect of progesterone and calcitriol on CYP24A1 and its spliced variant expression in endometrial cancer cell lines and correlated this with tumor cell growth. Expression of CYP24A1 was assessed in tissue microarrays by immunohistochemistry. A grade-dependent increase of CYP24A1 expression was found in endometrial carcinomas. Endometrial cancer cells expressed high levels of CYP24A1 compared to immortalized endometrial epithelial cells. Furthermore, CYP24A1 is induced in cells in response to calcitriol. Regulation of CYP24A1 by progesterone, progestin derivatives, calcitriol and their combination was examined by RT-PCR and Western blotting following 8, 24, 72 and 120 h exposure of cells to hormones. In all cancer cell lines, progesterone, medroxyprogesterone acetate and norgestrol attenuatedcalcitriol-induced CYP24A1, spliced variant CYP24SV transcripts and protein expression at 72 and 120 h of treatment. Furthermore, knockdown of CYP24A1 gene expression by siRNA se...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Biology Source Type: research