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

2013 ◽  
Vol 23 (1) ◽  
pp. 52-59 ◽  
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.

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

2006 ◽  
Vol 20 (3) ◽  
pp. 631-646 ◽  
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.

scholarly journals G Protein-Coupled Receptor 87 (GPR87) Promotes Cell Proliferation in Human Bladder Cancer Cells

2015 ◽  
Vol 16 (10) ◽  
pp. 24319-24331 ◽  
Author(s):  
Xia Zhang ◽  
Dage Liu ◽  
Yushi Hayashida ◽  
Homare Okazoe ◽  
Takeshi Hashimoto ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bladder Cancer ◽  
Cancer Cells ◽  
G Protein ◽  
Human Bladder Cancer ◽  
G Protein Coupled Receptor ◽  
Human Bladder ◽  
Bladder Cancer Cells ◽  
G Protein Coupled ◽  
Human Bladder Cancer Cells

GRP137 promotes cell proliferation and metastasis through regulation of the PI3K/AKT pathway in human ovarian cancer

2018 ◽  
Vol 104 (5) ◽  
pp. 330-337 ◽  
Author(s):  
Li-qian Zhang ◽  
Su-qing Yang ◽  
Xiang-dong Qu ◽  
Xian-jun Chen ◽  
Hong-sheng Lu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
G Protein ◽  
Biological Activities ◽  
Xenograft Model ◽  
Akt Pathway ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
G Protein Coupled Receptor ◽  
Skov3 Cells ◽  
G Protein Coupled

Purpose: Ovarian cancer is one of the leading causes of death for women worldwide. The present study aims to investigate the role of G protein-coupled receptor 137 (GPR137) in the biological activities of ovarian cancer cells. Methods: (QUERY: Please supply Methods for Abstract) Results: G protein-coupled receptor 137 was highly expressed in clinical ovarian cancer tissues and exhibited the highest protein levels in SKOV3 cells and OVCAR3 cells. Knockdown of GPR137 caused significant decreases in cell proliferative rates and colony formation abilities in SKOV3 cells and OVCAR3 cells and also inhibited the in vivo tumorigenesis in a xenograft model. It was observed that knockdown of GPR137 inhibited cell motility by up to 40% in SKOV3 cells and approximately 65% in OVCAR3 cells in wound-healing assay. Cell migration abilities were consistently inhibited by 68.2% in SKOV3 cells and 59.3% in OVCAR3 cells, whereas cell invasion abilities were inhibited by 64.0% and 74.2% in SKOV3 and OVCAR3 cells, respectively, after knockdown of GPR137. When GPR137 was depleted, epithelial markers were increased, while mesenchymal markers decreased. Conclusions: Our data suggest that GPR137 plays pro-oncogenic roles in ovarian cancer via regulation of the PI3K/AKT pathway. These observations might pave new insights into therapeutic strategies against human ovarian cancer.

Human herpesvirus KSHV encodes a constitutively active G-protein-coupled receptor linked to cell proliferation

Nature ◽  
1997 ◽  
Vol 385 (6614) ◽  
pp. 347-350 ◽  
Author(s):  
Leandros Arvanitakis ◽  
Elizabeth Geras-Raaka ◽  
Anjali Varma ◽  
Marvin C. Gershengorn ◽  
Ethel Cesarman
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Human Herpesvirus ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Constitutively Active

scholarly journals Leucine-rich repeat-containing G-protein-coupled receptor 8 in mature glomeruli of developing and adult rat kidney and inhibition by insulin-like peptide-3 of glomerular cell proliferation

2006 ◽  
Vol 189 (2) ◽  
pp. 397-408 ◽  
Author(s):  
P Fu ◽  
P-J Shen ◽  
C-X Zhao ◽  
D J Scott ◽  
C S Samuel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
G Protein ◽  
Binding Sites ◽  
Renal Cortex ◽  
Mesangial Cells ◽  
Rat Kidney ◽  
Leucine Rich Repeat ◽  
G Protein Coupled Receptor ◽  
Adult Rat ◽  
G Protein Coupled

Leucine-rich repeat-containing G-protein-coupled receptor 8 (LGR8, or RXFP2) is a member of the type C leucine-rich repeat-containing G protein-coupled receptor family, and its endogenous ligand is insulin-like peptide-3 (INSL3). Although LGR8 expression has been demonstrated in various human tissues, including testis, ovary, brain and kidney, the precise roles of this receptor in many of these tissues are unknown. In an effort to better understand INSL3–LGR8 systems in the rat, we cloned the full-length Lgr8 cDNA and investigated the presence and cellular localization of Lgr8 mRNA expression in adult and developing rat kidney. On the basis of these findings, we investigated the presence and distribution of renal 125I-labelled human INSL3-binding sites and the nature of INSL3–LGR8 signalling in cultured renal cells. Thus, using in situ hybridization histochemistry, cells expressing Lgr8 mRNA were observed in glomeruli of renal cortex from adult rats and were tentatively identified as mesangial cells. Quantitative, real-time PCR analysis of the developmental profile of Lgr8 mRNA expression in kidney revealed highest relative levels at late stage gestation (embryonic day 18), with a sharp decrease after birth and lowest levels in the adult. During development, silver grains associated with Lgr8 mRNA hybridization were observed overlying putative mesangial cells in mature glomeruli, with little or no signal associated with less-mature glomeruli. In adult and developing kidney, specific 125I-INSL3-binding sites were associated with glomeruli throughout the renal cortex. In primary cultures of glomerular cells, synthetic human INSL3 specifically and dose-dependently inhibited cell proliferation over a 48 h period, further suggesting the presence of functional LGR8 (receptors) on these cells (mesangial and others). These findings suggest INSL3–LGR8 signalling may be involved in the genesis and/or developmental maturation of renal glomeruli and possibly in regulating mesangial cell density in adult rat kidney.

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