title: Activation of G protein-coupled receptor 30 by thiodiphenol promotes proliferation of estrogen receptor α-positive breast cancer cells.
abstract: Many studies have been shown that environmental estrogen bisphenol A (BPA) can activate nuclear receptor (estrogen receptor alpha, ERα) 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 ERα and GPR30-mediated phosphatidylinotidol 3-kinase/protein kinase B (PI3K/AKT) and extracellular-signa1regulated kinase (ERK1/2) signaling pathways. The results showed that exposure to 0.1-10 μM 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 μM TDP significantly increased the expression of ERα, GPR30, p-AKT and p-ERK1/2 protein. Specific protein inhibitors blocked phosphorylation of ERK1/2 and AKT 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 ERα stimulated MCF-7 cell proliferation. Our results indicate a novel mechanism through which TDP may exert relevant estrogenic action in ERα positive cancer cells.
authors.affiliation: Institute of Environmental Pollution and Health, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China. Electronic address: leibingli@shu.edu.cn.
authors.forename: Bingli
authors.initials: B
authors.lastname: Lei
authors.affiliation: Institute of Environmental Pollution and Health, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.affiliation: Institute of Environmental Pollution and Health, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Institute of Environmental Pollution and Health, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Minghong
authors.initials: M
authors.lastname: Wu
authors.affiliation: Institute of Environmental Pollution and Health, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Institute of Environmental Pollution and Health, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Organic Geochemistry, Guangdong Key Laboratory of Environment and Resources, Guangzhou Institute of Geochemistry, Chinese Academy of Sciences, Guangzhou 510640, China. Electronic address: zhiqiang@gig.ac.cn.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Institute of Environmental Pollution and Health, College of Environmental and Chemical Engineering, Shanghai University, Shanghai 200444, China.
authors.forename: Yipei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D005260:Female; D006801:Humans; D001559:Benzhydryl Compounds; D001943:Breast Neoplasms; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology; D015386:Hazardous Substances / Q000633:toxicity; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D048052:Mitogen-Activated Protein Kinase 3; D019800:Phenol / Q000633:toxicity; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; C006780:bisphenol A; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; C109584:GPER1 protein, human; D015386:Hazardous Substances; D048052:Mitogen-Activated Protein Kinase 3; D019800:Phenol; D010636:Phenols; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; C069693:bis(4-oxyphenyl)sulfide; D000098826:Bisphenol A Compounds
keywords: Biological effect; Estrogen receptor; MCF-7 cells; Molecular mechanism; TDP