GnRH signaling in intrauterine tissues

Type I GnRH (GnRH-I, GNRH1) and type II GnRH (GnRH-II, GNRH2), each encoded by separate genes, have been identified in humans. The tissue distribution and functional regulation of GnRH-I and GnRH-II clearly differ despite their comparable cDNA and genomic structures. These hormones exert their effects by binding to cell surface transmembrane G protein coupled receptors and stimulating the Gq/11 subfamily of G proteins. The hypothalamus and pituitary are the main origin and target sites of GnRH, but numerous studies have demonstrated that extra-hypothalamic GnRH and extra-pituitary GnRH receptors exist in different reproductive tissues such as the ovary, endometrium, placenta, and endometrial cancer cells. In addition to endocrine regulation, GnRH is also known to act in an autocrine and paracrine manner to suppress cell proliferation and activate apoptosis in the endometrium and endometrial cancer cells through several mechanisms. Both GnRH-I and GnRH-II exhibit regulatory roles in tissue remodelling during embryo implantation and placentation, which suggests that these hormones may have important roles in embryo implantation and early pregnancy. The presence of varied GnRH and GnRH receptor systems demonstrate their different roles in distinct tissues using dissimilar mechanisms. These may result in the generation of new GnRH analogues used for several hormone-related diseases.

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The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2012.02.161 ◽

2012 ◽

Vol 420 (2) ◽

pp. 343-349 ◽

Cited By ~ 41

Author(s):

Gui-Qiang Du ◽

Long Zhou ◽

Xiao-Yue Chen ◽

Xiao-Ping Wan ◽

Yin-Yan He

Keyword(s):

Endometrial Cancer ◽

Cancer Cells ◽

G Protein ◽

G Protein Coupled Receptor ◽

G Protein Coupled

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Serum Prolactin Contributes to Enhancing Prolactin Receptor and pJAK2 in Type I Endometrial Cancer Cells in Young Women Without Insulin Resistance

International Journal of Gynecological Pathology ◽

10.1097/pgp.0000000000000527 ◽

2019 ◽

Vol 38 (4) ◽

pp. 318-325 ◽

Cited By ~ 1

Author(s):

Chimeddulam Erdenebaatar ◽

Munekage Yamaguchi ◽

Mahina Monsur ◽

Fumitaka Saito ◽

Ritsuo Honda ◽

...

Keyword(s):

Insulin Resistance ◽

Endometrial Cancer ◽

Cancer Cells ◽

Young Women ◽

Prolactin Receptor ◽

Serum Prolactin ◽

Type I

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The G Protein–Coupled Receptor GPR30 Mediates the Nontranscriptional Effect of Estrogen on the Activation of PI3K/Akt Pathway in Endometrial Cancer Cells

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e31827912b8 ◽

2013 ◽

Vol 23 (1) ◽

pp. 52-59 ◽

Cited By ~ 32

Author(s):

Xin Ge ◽

Ruixia Guo ◽

Yuhuan Qiao ◽

Yancai Zhang ◽

Jia Lei ◽

...

Keyword(s):

Cell Proliferation ◽

Endometrial Cancer ◽

Cancer Cells ◽

G Protein ◽

Akt Pathway ◽

G Protein Coupled Receptor ◽

Down Regulation ◽

Phosphorylated Akt ◽

Ishikawa Cells ◽

G Protein Coupled

ObjectiveThe goal of this study was to investigate the effect of G protein–coupled receptor 30 (GPR30) on the activation of PI3K/Akt pathway induced by E2 in endometrial cancer cells.Methods and materialsImmunohistochemistry was performed to determine the location and expression of GPR30, estrogen receptors (ERs), Akt, and phosphorylated Akt. We also investigated the expression of GPR30, ERs, and the level of phosphorylation of Akt induced by E2 in endometrial cancer cells, Ishikawa cells, and HEC-1A cells. We down-regulated the expression of GPR30 in endometrial cancer cell lines by transfection with shGPR30-pGFP-V-RS, a GPR30 antisense expression vector. The cells were then subjected to a proliferation assay. Immunoprecipitation assay was performed to determine whether GPR30 directly bind to PI3K. The stable transfected cells resuspension of 100 μL (5 × 106 cells) was injected subcutaneously into the right flank of athymic mice to perform xenograft tumor formation assays.ResultsE2 stimulated cell proliferation and induced GPR30 expression and PI3K/Akt pathway activation in endometrial cancer cells, Ishikawa cells, and HEC-1A cells, whereas the expression of ERs remained unchangeable. Down-regulation of GPR30 decreased the phosphorylation of Akt and reduced cell proliferation, and GPR30 did not bind to PI3K. Down-regulation of GPR30 significantly inhibited the tumor growth of HEC-1A cells in athymic nude mice.ConclusionsThese findings suggest that GPR30 mediates the nontranscriptional effect of estrogen on the activation of PI3K/Akt pathway in endometrial cancer cells.

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Ca 2+ channel subunit α 1D promotes proliferation and migration of endometrial cancer cells mediated by 17β‐estradiol via the G protein‐coupled estrogen receptor

The FASEB Journal ◽

10.1096/fj.14-265603 ◽

2015 ◽

Vol 29 (7) ◽

pp. 2883-2893 ◽

Cited By ~ 28

Author(s):

Juan Hao ◽

Xiaoxia Bao ◽

Bo Jin ◽

Xiujuan Wang ◽

Zebin Mao ◽

...

Keyword(s):

Estrogen Receptor ◽

Endometrial Cancer ◽

Cancer Cells ◽

G Protein ◽

17Β Estradiol ◽

And Migration ◽

G Protein Coupled ◽

Proliferation And Migration

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The G Protein-Coupled Receptor GPR30 Mediates the Proliferative Effects Induced by 17β-Estradiol and Hydroxytamoxifen in Endometrial Cancer Cells

Molecular Endocrinology ◽

10.1210/me.2005-0280 ◽

2006 ◽

Vol 20 (3) ◽

pp. 631-646 ◽

Cited By ~ 249

Author(s):

Adele Vivacqua ◽

Daniela Bonofiglio ◽

Anna Grazia Recchia ◽

Anna Maria Musti ◽

Didier Picard ◽

...

Keyword(s):

Endometrial Cancer ◽

Cancer Cells ◽

G Protein ◽

Cell Lines ◽

Phosphatidylinositol 3 Kinase ◽

G Protein Coupled Receptor ◽

17Β Estradiol ◽

Agonistic Activity ◽

G Protein Coupled ◽

Phosphatidylinositol 3

Abstract The growth of both normal and transformed epithelial cells of the female reproductive system is stimulated by estrogens, mainly through the activation of estrogen receptor α (ERα), which is a ligand-regulated transcription factor. The selective ER modulator tamoxifen (TAM) has been widely used as an ER antagonist in breast tumor; however, long-term treatment is associated with an increased risk of endometrial cancer. To provide new insights into the potential mechanisms involved in the agonistic activity exerted by TAM in the uterus, we evaluated the potential of 4-hydroxytamoxifen (OHT), the active metabolite of TAM, to transactivate wild-type ERα and its splice variant expressed in Ishikawa and HEC1A endometrial tumor cells, respectively. OHT was able to antagonize only the activation of ERα by 17β-estradiol (E2) in Ishikawa cells, whereas it up-regulated c-fos expression in a rapid manner similar to E2 and independently of ERα in both cell lines. This stimulation occurred through the G protein-coupled receptor named GPR30 and required Src-related and epidermal growth factor receptor tyrosine kinase activities, along with the activation of both ERK1/2 and phosphatidylinositol 3-kinase/AKT pathways. Most importantly, OHT, like E2, stimulated the proliferation of Ishikawa as well as HEC1A cells. Transfecting a GPR30 antisense expression vector in both endometrial cancer cell lines, OHT was no longer able to induce growth effects, whereas the proliferative response to E2 was completely abrogated only in HEC1A cells. Furthermore, in the presence of the inhibitors of MAPK and phosphatidylinositol 3-kinase pathways, PD 98059 and wortmannin, respectively, E2 and OHT did not elicit growth stimulation. Our data demonstrate a new mode of action of E2 and OHT in endometrial cancer cells, contributing to a better understanding of the molecular mechanisms involved in their uterine agonistic activity.

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