Abstract
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.
Highlights
G-protein-coupled receptor (GPCR), the largest family of cell signaling receptors, are seven transmembrane receptors that respond to numerous types of extracellular signals and regulate many physiological processes [1]
We recently reported that various human cancers—including CLL cells/stromal cells associated with CLL, colon and breast cancer cell lines, pancreatic ductal adenocarcinoma (PDAC) cells, PDAC tumors, and cancer associated fibroblasts (CAFs)—express from 50 to more than 100 GPCRs [7]
GPR68 is expressed in numerous human tumors, including PDAC tumors and primary PDAC CAFs [24], gastrointestinal stromal tumors (GIST) and appendiceal tumor CAFs [24], colon cancer CAFs [60], anaplastic thyroid cancer (FRO) cells [26], osteosarcoma MG63 cells [22], medulloblastoma tissue [61] and medulloblastoma cell line DAOY [62], Merkel cell carcinoma (MCC), dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX), and pleomorphic dermal sarcoma (PDS) [63]
Summary
GPCRs, the largest family of cell signaling receptors (with over 800 GPCRs encoded in the human genome, ~3% of the human genome), are seven transmembrane receptors that respond to numerous types of extracellular signals (e.g., biogenic amines, lipids, peptides, proteins, ions, photons, etc.) and regulate many physiological processes [1]. These include key functional responses, such as neurotransmission, sensory perception, cell metabolism, and differentiation [2]. GPR68 was identified as a proton-sensing GPCR, inactive at pH 7.8 but fully activated at pH 6.8, as measured by inositol phosphate (IP) formation [22]
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