Estrogen Receptor-β Mediates the Inhibition of DLD-1 Human Colon Adenocarcinoma Cells by Soy Isoflavones

To understand the relationship between the role of soy isoflavones and estrogen receptor (ER)-beta 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-beta 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)-kappa B. 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 upregulation of its inhibitor p21(cip1) expressions. ER-beta gene silencing lowered soy isoflavone-mediated suppression of cell viability and proliferation. ERK-1/2 and AKT expressions were unaltered and NF-kappa B was modestly upregulated by soy isoflavones after transient knockdown of ER-beta expression. Soy isoflavone-mediated arrest of cells at G2/M phase and upregulation of p21(cip1) expression were not observed when ER-beta gene was silenced. These findings suggest that maintaining the expression of ER-beta is crucial in mediating the growth-suppressive effects of soy isoflavones against colon tumors. Thus upregulation of ER-beta status by specific food-borne ER-ligands such as soy isoflavones could potentially be a dietary prevention or therapeutic strategy for colon cancer.