title: Nuclear estrogen receptor-mediated Notch signaling and GPR30-mediated             PI3K/AKT signaling in the regulation of endometrial cancer cell proliferation.
abstract: To elucidate the mechanisms of nuclear estrogen receptor (ER)-mediated and             G protein-coupled receptor 30 (GPR30)-mediated signaling in the regulation of             proliferation in ER-positive and ER-negative endometrial cancer cells, two human             endometrial carcinoma cell lines, Ishikawa (ER-positive) and KLE (ER-negative),             were used. PCR and Western blot analyses were used to determine the effects of             estrogen stimulation on the activation of Notch and GPR30-PI3K/AKT signaling.             Cell growth was investigated using MTT assays. Overexpression of ER in ER-negative             cells was achieved by plasmid transfection and was used to investigate the effects             on cellular growth and Notch signaling. GPR30-mediated signaling was evaluated             using siRNA interference. Estrogen stimulated cell proliferation in both cell             lines, it activated Notch signaling in ER-positive Ishikawa cells, but not in             ER-negative KLE cells. Blockade of this signaling by a Notch inhibitor resulted             in partial arrest of estrogen-induced cell proliferation in Ishikawa cells. Overexpression             of ER in KLE cells restored estrogen-enhanced Notch signaling and further promoted             cell growth. GPR30, as a new G-protein-coupled estrogen receptor, was detected             in both cell lines, but was stronger in ER-negative KLE cells. Depletion of GPR30             in KLE cells abolished estrogen-induced PI3K/AKT signaling activation and resulted             in inhibition of cell proliferation. Conclusively, regulation of proliferation             in nuclear ER-positive endometrial cancer cells is mediated by both ER-Notch signaling             and GPR30-PI3K/AKT signaling, whereas only the latter pathway is involved in the             regulation of growth in nuclear ER-negative endometrial cancer cells.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai, PR China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wei
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wu
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhou
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xi
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhu
authors.forename: Youji
authors.initials: Y
authors.lastname: Feng
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D004965:Estrogen Antagonists; C109584:GPER1 protein, human; D051881:Receptor, Notch1; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D000077267:Fulvestrant; D004958:Estradiol; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt