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.