Phytoestrogens and 17beta-estradiol influence vitamin D metabolism and receptor expression-relevance for colon cancer prevention.
1alpha,25(OH)2D3 is a potent growth inhibitor of different cancer cell lines. The steroid hormone is not only synthesized in the kidney, but also at extrarenal sites. Unfortunately, this potential autocrine/paracrine defense mechanism is lost during the late stages of colon tumor progression. It is therefore desirable to find a pharmacological means to maintain or enhance endogenous production of 1alpha,25(OH)2D3 during early periods in tumorigenesis. The phytoestrogen genistein was shown to regulate different cytochrome P450 enzymes, a family of proteins to which both of the vitamin D-metabolizing CYP27B1 (1alpha-hydroxylase) and CYP24 (24-hydroxylase) belong. Therefore, we used two colon cancer cell lines, Caco-2 and COGA-1, and investigated possible influences of genistein on different parameters of extrarenal vitamin D metabolism by HPLC, RT-PCR, and Western blot analysis. Differences between the two cell lines were found in both their basic enzymatic activities and in their response to treatment with 1alpha,25(OH)2D3. Whereas Caco-2 cells responded to administration of 100 nM genistein with a down-regulation of 24-hydroxylase activity, COGA-1 cells showed not only a significant down-regulation of 24-hydroxylase protein expression, but also a clear induction of vitamin D receptor (VDR) expression. Similar effects on VDR expression were achieved by administration of 10 nM 17beta-estradiol. This suggests an estrogenic mode of action of genistein, which might be dependent on differential distribution of estrogen receptors alpha and beta in our cell lines.
Lechner
Daniel
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Institute of Pathophysiology, University of Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria. daniel.lechner@akh-wien.ac.at
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D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000517:prevention & control*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D048789:Phytoestrogens; D028321:Plant Preparations / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism*
D000970:Antineoplastic Agents; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018167:Receptors, Calcitriol; D014807:Vitamin D; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D019833:Genistein