Activation of G protein-coupled receptor 30 by thiodiphenol promotes proliferation of estrogen receptor alpha-positive breast cancer cells

摘要

Many studies have been shown that environmental estrogen bisphenol A (BPA) can activate nuclear receptor (estrogen receptor alpha, ER alpha) or membrane receptor (G-protein-coupled receptor, GPR30) in breast cancer cells and exerts genomic or nongenomic actions inducing cell proliferation. 4,4'-thiodiphenol (TDP) as one of BPA derivatives exhibits more potent estrogenic activity than BPA does. However, comparatively little is known about the ways in which TDP interferes with these signaling pathways and produces cell biological changes. This study evaluated the effect of TDP on cell viability, reactive oxygen species (ROS) formation, and intercellular calcium (Ca2+) fluctuation in MCF-7 breast cancer cells. The underlying molecular mechanism of cell proliferation induced by TDP was analyzed by examining the activation of ER alpha and GPR30-mediated phosphatidylinotidol 3-kinase/protein kinase B (PI3K/AKT) and extracellular-signal regulated kinase (ERK1 /2) signaling pathways. The results showed that exposure to 0.1-10 mu M TDP for 24, 48, and 72 h significantly increased viability of MCF-7 cells. At the same concentration range, TDP exposure for 3 and 24 h markedly elevated ROS production and intracellular Ca2+ levels. In addition, 0.01-1 mu M TDP significantly increased the expression of ER alpha, GPR30, p-AKT and p-ERK1 /2 protein. Specific protein inhibitors blocked phosphorylation of ERK1 /2 and AU and decreased TDP-induced cell proliferation. These findings show that TDP activated the GPR30-PI3K/AKT and ERK1/2 pathways, and the resulting interaction with ERa stimulated MCF-7 cell proliferation. Our results indicate a novel mechanism through which TDP may exert relevant estrogenic action in ERa positive cancer cells. (C) 2016 Elsevier Ltd. All rights reserved.