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      G-Protein-Coupled Estrogen Receptor Antagonist G15 Decreases Estrogen-Induced Development of Non-Small Cell Lung Cancer

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          Abstract

          G-protein-coupled estrogen receptor (GPER) was found to promote non-small cell lung cancer (NSCLC) by estrogen, indicating the potential necessity of inhibiting GPER by a selective antagonist. This study was performed to elucidate the function of GPER-selective inhibitor G15 in NSCLC development. Cytoplasmic GPER (cGPER) and nuclear GPER (nGPER) were detected by immunohistochemical analysis in NSCLC samples. The relation of GPER and estrogen receptor β (ERβ) expression and correlation between GPER, ERβ, and clinical factors were analyzed. The effects of activating GPER and function of G15 were analyzed in the proliferation of A549 and H1793 cell lines and development of urethane-induced adenocarcinoma. Overexpression of cGPER and nGPER was detected in 80.49% (120/150) and 52.00% (78/150) of the NSCLC samples. High expression of GPER was related with higher stages, poorer differentiation, and high expression of ERβ. The protein level of GPER in the A549 and H1793 cell lines was increased by treatment with E2, G1 (GPER agonist), or fulvestrant (Ful; ERβ antagonist) and decreased by G15. Administration with G15 reversed the E2- or G1-induced cell growth by inhibiting GPER. In urethane-induced adenocarcinoma mice, the number of tumor nodules and tumor index increased in the E2 or G1 group and decreased by treatment with G15. These findings demonstrate that using G15 to block GPER signaling may be considered as a new therapeutic target in NSCLC.

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          Most cited references40

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          Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF.

          Estrogen rapidly activates the mitogen-activated protein kinases, Erk-1 and Erk-2, via an as yet unknown mechanism. Here, evidence is provided that estrogen-induced Erk-1/-2 activation occurs independently of known estrogen receptors, but requires the expression of the G protein-coupled receptor homolog, GPR30. We show that 17beta-estradiol activates Erk-1/-2 not only in MCF-7 cells, which express both estrogen receptor alpha (ER alpha) and ER beta, but also in SKBR3 breast cancer cells, which fail to express either receptor. Immunoblot analysis using GPR30 peptide antibodies showed that this estrogen response was associated with the presence of GPR30 protein in these cells. MDA-MB-231 breast cancer cells (ER alpha-, ER beta+) are GPR30 deficient and insensitive to Erk-1/-2 activation by 17beta-estradiol. Transfection of MDA-MB-231 cells with a GPR30 complementary DNA resulted in overexpression of GPR30 protein and conversion to an estrogen-responsive phenotype. In addition, GPR30-dependent Erk-1/-2 activation was triggered by ER antagonists, including ICI 182,780, yet not by 17alpha-estradiol or progesterone. Consistent with acting through a G protein-coupled receptor, estradiol signaling to Erk-1/-2 occurred via a Gbetagamma-dependent, pertussis toxin-sensitive pathway that required Src-related tyrosine kinase activity and tyrosine phosphorylation of tyrosine 317 of the Shc adapter protein. Reinforcing this idea, estradiol signaling to Erk-1/-2 was dependent upon trans-activation of the epidermal growth factor (EGF) receptor via release of heparan-bound EGF (HB-EGF). Estradiol signaling to Erk-1/-2 could be blocked by: 1) inhibiting EGF-receptor tyrosine kinase activity, 2) neutralizing HB-EGF with antibodies, or 3) down-modulating HB-EGF from the cell surface with the diphtheria toxin mutant, CRM-197. Our data imply that ER-negative breast tumors that continue to express GPR30 may use estrogen to drive growth factor-dependent cellular responses.
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            The different roles of ER subtypes in cancer biology and therapy.

            By eliciting distinct transcriptional responses, the oestrogen receptors (ERs) ERα and ERβ exert opposite effects on cellular processes that include proliferation, apoptosis and migration and that differentially influence the development and the progression of cancer. Perturbation of ER subtype-specific expression has been detected in various types of cancer, and the differences in the expression of ERs are correlated with the clinical outcome. The changes in the bioavailability of ERs in tumours, together with their specific biological functions, promote the selective restoration of their activity as one of the major therapeutic approaches for hormone-dependent cancers.
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              A transmembrane intracellular estrogen receptor mediates rapid cell signaling.

              The steroid hormone estrogen regulates many functionally unrelated processes in numerous tissues. Although it is traditionally thought to control transcriptional activation through the classical nuclear estrogen receptors, it also initiates many rapid nongenomic signaling events. We found that of all G protein-coupled receptors characterized to date, GPR30 is uniquely localized to the endoplasmic reticulum, where it specifically binds estrogen and fluorescent estrogen derivatives. Activating GPR30 by estrogen resulted in intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. Thus, GPR30 represents an intracellular transmembrane estrogen receptor that may contribute to normal estrogen physiology as well as pathophysiology.
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                Author and article information

                Journal
                Oncol Res
                Oncol Res
                OR
                Oncology Research
                Cognizant Communication Corporation (Elmsford, NY )
                0965-0407
                1555-3906
                2019
                21 February 2019
                : 27
                : 3
                : 283-292
                Affiliations
                [1]*Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, P.R. China
                [2]†Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, P.R. China
                [3]‡Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, P.R. China
                [4]§Department of Respiratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei Province, P.R. China
                Author notes
                Address correspondence to Yongde Liao, Department of Thoracic Surgery, Tongji Hospital, 1095 Jiefang Dadao Street, Wuhan, Hubei Province 430030, P.R. China. E-mail: liaotjxw@ 123456126.com
                Article
                OR1220
                10.3727/096504017X15035795904677
                7848463
                28877783
                c21f6838-b9cc-4fa9-85f1-142939ca5cd7
                Copyright © 2019 Cognizant, LLC.

                This article is licensed under a Creative Commons Attribution-NonCommercial NoDerivatives 4.0 International License.

                History
                Page count
                Figures: 5, Tables: 2, References: 40, Pages: 10
                Categories
                Article

                g15,g-protein-coupled estrogen receptor (gper),non-small cell lung cancer (nsclc),g1,e2

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