Induced growth of BG-1 ovarian cancer cells by 17 beta-estradiol or various endocrine disrupting chemicals was reversed by resveratrol via downregulation of cell cycle progression

Abstract

Resveratrol (trans-3,4',5-trihydroxystilbene; RES), a phytoestrogen, exists in grape skin and red wine. Endocrine disrupting chemicals (EDCs) appear to promote the development and progression of estrogen-dependent cancers. In this study, we evaluated the inhibitory effect of RES on the cell proliferation induced by various EDCs in BG-1 ovarian cancer cells. Various EDCs, such as bisphenol A (BPA), nonylphenol (NP), octylphenol (OP), methoxychlor (MXC) and hexabromocyclododecane (HBCD), were employed in this study. In the in vitro experiments, treatment of BG-1 cells with E2, BPA, NP, OP, MXC or HBCD resulted in an increase of cell growth. By contrast, increased cell viability induced by these EDCs was reversed when co-cultured with RES. In addition, we examined the regulation of cell cycle-related genes by RT-PCR and western blot analysis. Treatment with each EDC was found to decrease only the gene expression of p21 and increase the expression of cell cycle-dependent kinase 2 (CDK2). However, co-treatment with RES and each EDC resulted in an increased gene expression of p21 and a decreased expression of CDK2. Cyclin D1 was increased by downregulating p21 only when treated with each EDC in the absence of RES, while co-treatment with RES and each EDC decreased the gene expression of cyclin D1 by upregulating p21. Taken together, RES appears to be an inhibitor of cyclin D1 and CDK2 and is responsible for the cell cycle arrest at the G, phase. In addition, when co-treated with each EDC, RES increased the expression of p21 and resulted in the growth inhibition of BG-1 ovarian cancer cells. Taken together, these results indicate the antiproliferative effect of RES, a dietary phytoestrogen, on estrogen-dependent ovarian cancer cells activated by EDCs.