GPR68: An Emerging Drug Target in Cancer

GPR68 (or ovarian cancer G protein-coupled receptor 1, OGR1) is a proton-sensing G-protein-coupled receptor (GPCR) that responds to extracellular acidity and regulates a variety of cellular functions. Acidosis is considered a defining hallmark of the tumor microenvironment (TME). GPR68 expression is highly upregulated in numerous types of cancer. Emerging evidence has revealed that GPR68 may play crucial roles in tumor biology, including tumorigenesis, tumor growth, and metastasis. This review summarizes current knowledge regarding GPR68—its expression, regulation, signaling pathways, physiological roles, and functions it regulates in human cancers (including prostate, colon and pancreatic cancer, melanoma, medulloblastoma, and myelodysplastic syndrome). The findings provide evidence for GPR68 as a potentially novel therapeutic target but in addition, we note challenges in developing drugs that target GPR68.

Download Full-text

Faculty Opinions recommendation of GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1047096.498149 ◽

2006 ◽

Author(s):

Michael Schön

Keyword(s):

Tumor Growth ◽

G Protein ◽

Tissue Transglutaminase ◽

G Protein Coupled Receptor ◽

Melanoma Tumor ◽

Tumor Growth And Metastasis ◽

G Protein Coupled

Download Full-text

Manganese and cobalt activate zebrafish ovarian cancer G-protein-coupled receptor 1 but not GPR4

Journal of Receptors and Signal Transduction ◽

10.1080/10799893.2017.1298130 ◽

2017 ◽

Vol 37 (4) ◽

pp. 401-408 ◽

Cited By ~ 5

Author(s):

Jun Negishi ◽

Yuka Omori ◽

Mami Shindo ◽

Hayate Takanashi ◽

Shiori Musha ◽

...

Keyword(s):

Ovarian Cancer ◽

G Protein ◽

G Protein Coupled Receptor ◽

G Protein Coupled

Download Full-text

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

Tumori Journal ◽

10.5301/tj.5000703 ◽

2018 ◽

Vol 104 (5) ◽

pp. 330-337 ◽

Cited By ~ 4

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.

Download Full-text

Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Endocrinology ◽

10.1210/en.2012-1164 ◽

2012 ◽

Vol 153 (9) ◽

pp. 4171-4180 ◽

Cited By ~ 27

Author(s):

Takashi Nakakura ◽

Chihiro Mogi ◽

Masayuki Tobo ◽

Hideaki Tomura ◽

Koichi Sato ◽

...

Keyword(s):

Ovarian Cancer ◽

Insulin Secretion ◽

G Protein ◽

Normal Glucose Tolerance ◽

Extracellular Ph ◽

G Protein Coupled Receptor ◽

Glucose Stimulated Insulin Secretion ◽

G Protein Coupled

Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown as a receptor for protons. In the present study, we aimed to know whether OGR1 plays a role in insulin secretion and, if so, the manner in which it does. To this end, we created OGR1-deficient mice and examined insulin secretion activity in vivo and in vitro. OGR1 deficiency reduced insulin secretion induced by glucose administered ip, although it was not associated with glucose intolerance in vivo. Increased insulin sensitivity and reduced plasma glucagon level may explain, in part, the unusual normal glucose tolerance. In vitro islet experiments revealed that glucose-stimulated insulin secretion was dependent on extracellular pH and sensitive to OGR1; insulin secretion at pH 7.4 to 7.0, but not 8.0, was significantly suppressed by OGR1 deficiency and inhibition of Gq/11 proteins. Insulin secretion induced by KCl and tolbutamide was also significantly inhibited, whereas that induced by several insulin secretagogues, including vasopressin, a glucagon-like peptide 1 receptor agonist, and forskolin, was not suppressed by OGR1 deficiency. The inhibition of insulin secretion was associated with the reduction of glucose-induced increase in intracellular Ca2+ concentration. In conclusion, the OGR1/Gq/11 protein pathway is activated by extracellular protons existing under the physiological extracellular pH of 7.4 and further stimulated by acidification, resulting in the enhancement of insulin secretion in response to high glucose concentrations and KCl.

Download Full-text

Molecular Actions of Ovarian Cancer G Protein-Coupled Receptor 1 Caused by Extracellular Acidification in Bone

International Journal of Molecular Sciences ◽

10.3390/ijms151222365 ◽

2014 ◽

Vol 15 (12) ◽

pp. 22365-22373 ◽

Cited By ~ 5

Author(s):

Feng-Lai Yuan ◽

Ming-Dong Zhao ◽

Li-Bo Jiang ◽

Hui-Ren Wang ◽

Lu Cao ◽

...

Keyword(s):

Ovarian Cancer ◽

G Protein ◽

G Protein Coupled Receptor ◽

Extracellular Acidification ◽

G Protein Coupled

Download Full-text

ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors

AJP Cell Physiology ◽

10.1152/ajpcell.00620.2005 ◽

2006 ◽

Vol 291 (1) ◽

pp. C1-C10 ◽

Cited By ~ 235

Author(s):

Haruhiko Ohtsu ◽

Peter J. Dempsey ◽

Satoru Eguchi

Keyword(s):

G Protein ◽

Egf Receptor ◽

Current Knowledge ◽

G Protein Coupled Receptors ◽

Surface Proteins ◽

Egf Receptors ◽

Cellular Functions ◽

Egfr Transactivation ◽

And Migration ◽

G Protein Coupled

A disintegrin and metalloprotease (ADAM) is a membrane-anchored metalloprotease implicated in the ectodomain shedding of cell surface proteins, including the ligands for epidermal growth factor (EGF) receptors (EGFR)/ErbB. It has been well documented that the transactivation of the EGFR plays critical roles for many cellular functions, such as proliferation and migration mediated through multiple G protein-coupled receptors (GPCRs). Recent accumulating evidence has suggested that ADAMs are the key metalloproteases activated by several GPCR agonists to produce a mature EGFR ligand leading to the EGFR transactivation. In this review, we describe the current knowledge on ADAMs implicated in mediating EGFR transactivation. The major focus of the review will be on the possible upstream mechanisms of ADAM activation by GPCRs as well as downstream signal transduction and the pathophysiological significances of ADAM-dependent EGFR transactivation.

Download Full-text