Phytoestrogens regulate transcription and translation of vitamin D receptor in colon cancer cells

Abstract

The present study assesses the effects of two isoflavones, genistein and glycitein, and equol -a product of intestinal bacterial metabolism of dietary isoflavones, on vitamin D receptor (VDR) expression in an intestinal HT29 cell line. Genistein and glycitein significantly upregulated the VDR transcription and translation in HT29 cells. The effect of equol was less pronounced.Treating HT29 cells transfected with a vector containing the VDR promoter next to a luciferase reporter with genistein or glycitein resulted in significant upregulation of VDR promoter activity, in a manner similar to that induced by 17b-estradiol (E2). Again, the effect of equol was less pronounced. VDR luciferase promoter activity was upregulated most by genistein, then by glycitein and least by equol when the VDR promoter was cotransfected with estrogen receptor b.Reporter gene and chromatin immunoprecipitation (ChIP) assays demonstrated that E2 upregulates AP-1 and Sp-1 sites present on the VDR gene. In contrast, the same assays demonstrated that the Sp-1, but not AP-1, site is induced by the phytoestrogens.Similar to E2, genistein, glycitein and the isoflavonoid metabolite equol induced higher concentrations of intracellular free calcium, an event that could provide the upstream mechanism(s) induced by E2 and phytoestrogens that initiates the signaling cascade which results in the activation of extracellular signal-regulated kinase (ERK) signaling pathways and modulation of Sp-1 sites of the VDR gene, and culminates in enhanced VDR expression.

The impact of vitamin D in breast cancer: genomics, pathways, metabolism

“…Further studies are therefore warranted to determine the degree to which estrogen status influences VDR abundance in different 1,25(OH) 2 D 3 target tissues (i.e., breast, bone, uterus), and whether common therapeutic synthetic or natural estrogens act as estrogen agonists or antagonists in regulation of VDR expression. Consistent with this concept, some data suggests that phytoestrogens such as resveratrol and genestein can alter VDR expression and 1,25(OH) 2 D 3 sensitivity in cancer cells in vitro (Wietzke and Welsh, 2003; Gilad et al, 2006). …”

Cell-Type-Specific Effects of Silibinin on Vitamin D-Induced Differentiation of Acute Myeloid Leukemia Cells Are Associated with Differential Modulation of RXRα Levels

“…A similar VDR protein upregulation in leukemia cells was observed when 1,25D was combined with other inducers or enhancers of differentiation, such as all trans retinoic acid (ATRA) [39] and bufalin [40], a major digoxin-like component of toad venom. Likewise, enhanced antiproliferative effects of 1,25D combinations with the soy isoflavone genistein [41–43] or the RRR stereoisomer of α -tocopherol [44] in nonleukemic cancer cells were associated with elevated VDR expression.…”

Bioactive Food Components, Inflammatory Targets, and Cancer Prevention

“…This is likely due to the known property of genistein that increases half-life of vitamin D by elevating the activity of its synthesizing enzyme CYP27B1 and inhibiting the activity of CYP24 that degrades vitamin D (56). Genistein (10 μmol/L) is also shown to increase vitamin D receptor expression by binding estrogen receptor β and thus facilitate the function of vitamin D in HT29 colon cancer cells (57). Therefore, nutritional supplementation of this soy isoflavone may optimize and/or enhance the cancer-preventive effects of vitamin D.…”