glycitein and Colonic-Neoplasms

To understand the relationship between the role of soy isoflavones and estrogen receptor (ER)-β in colon tumorigenesis, we investigated the cellular effects of soy isoflavones (composed of genistein, daidzein, and glycitein) in DLD-1 human colon adenocarcinoma cells with or without ER-β gene silencing by RNA interference (RNAi). Soy isoflavones decreased the expression of proliferating cell nuclear antigen (PCNA), extracellular signal-regulated kinase (ERK)-1/2, AKT, and nuclear factor (NF)-κB. Soy isoflavones dose-dependently caused G2/M cell cycle arrest and downregulated the expression of cyclin A. This was associated with inhibition of cyclin dependent kinase (CDK)-4 and up-regulation of its inhibitor p21(cip1) expressions. ER-β gene silencing lowered soy isoflavone-mediated suppression of cell viability and proliferation. ERK-1/2 and AKT expressions were unaltered and NF-κB was modestly upregulated by soy isoflavones after transient knockdown of ER-β expression. Soy isoflavone-mediated arrest of cells at G2/M phase and upregulation of p21(cip1) expression were not observed when ER-β gene was silenced. These findings suggest that maintaining the expression of ER-β is crucial in mediating the growth-suppressive effects of soy isoflavones against colon tumors. Thus upregulation of ER-β status by specific food-borne ER-ligands such as soy isoflavones could potentially be a dietary prevention or therapeutic strategy for colon cancer.

Topics: Adenocarcinoma; Anticarcinogenic Agents; Cell Cycle; Cell Proliferation; Colonic Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Estrogen Receptor beta; Genistein; Humans; Isoflavones; NF-kappa B

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 17beta-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 beta. 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.

Topics: Adenocarcinoma; Blotting, Western; Calcium; Colonic Neoplasms; Equol; Estradiol; Estrogen Receptor beta; Genistein; HT29 Cells; Humans; Immunoprecipitation; Isoflavones; Phytoestrogens; Promoter Regions, Genetic; Protein Biosynthesis; Receptors, Calcitriol; Reverse Transcriptase Polymerase Chain Reaction; Sp1 Transcription Factor; Transcription Factor AP-1; Transcription, Genetic; Transfection