Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway

Abstract

GPR56 is an orphan G protein -coupled receptor, mutations of which have recently been associated with bilateral frontoparietal polymicrogyria, a rare neurologic disease that has implications in brain development. However, no phenotype beyond central nervous system has yet been described for the GPR56-null mutations despite abundant GPR56 expression in many non -central nervous system adult tissues. In the present study, we show that higher GPR56 expression is correlated with the cellular transformation phenotypes of several cancer tissues compared with their normal counterparts, implying a potential oncogenic function. RNA interference -mediated GPR56 silencing results in apoptosis induction and reduced anchorage-independent growth of cancer cells via increased anoikis, whereas cDNA overexpression resulted in increased foci formation in mouse fibroblast NIH3T3 cell line. When GPR56 silencing was induced in vivo in several xenograft tumor models, significant tumor responses (including regression) were observed, suggesting the potential of targeting GPR56 in the development of tumor therapies. The expression profiling of GPR56-silenced A2058 melanoma cell line revealed several genes whose expression was affected by GPR56 silencing, particularly those in the integrin-mediated signaling and cell adhesion pathways. The potential role of GPR56 in cancer cell adhesion was further confirmed by the observation that GPR56 silencing also reduced cell adhesion to the extracellular matrix, which is consistent with the observed increase in anoikis and reduction in anchorage-independent growth phenotypes. The oncogenic potential and apparent absence of physiologic defects in adult human tissues lacking GPR56, as well as the targetable nature of G protein -coupled receptor by small molecule or antibody, make GPR56 an attractive drug target for the development of cancer therapies.

Promoter Methylation Profiles between Human Lung Adenocarcinoma Multidrug Resistant A549/Cisplatin (A549/DDP) Cells and Its Progenitor A549 Cells

“…G protein-coupled receptor 56 isoform 3 (GPR56) is an orphan G protein-coupled receptor that has been shown to be implicated in brain development and play various roles in endogenous cancer progression, 32) and suppress tumour growth and metastasis in human melanoma cell line xenograft models. 33) But their roles in MDR of lung cancer is still unclear. 34,35) Hence, this is the first study to report that the promoter methylation of these three genes was significantly higher in MDR cells of lung adenocarcinoma compared with its progenitor cells and the expression of these three genes was downregulated by the promoter hypermethylation.…”

International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors

“…On one hand, expression levels of ADGRG1 (GPR56) were found to be inversely correlated with the metastatic potential of melanoma cell lines (Zendman et al, 1999;Xu et al, 2006), and reexpression of the receptor led to a reduction in melanoma growth and metastasis . On the other hand, ADGRG1 (GPR56) was found to be upregulated in various cancer types (Shashidhar et al, 2005;Kausar et al, 2011) and in tumor cell lines (Ke et al, 2007), compared with normal samples.…”

Agonistic Antibodies Reveal the Function of GPR56 in Human Glioma U87-MG Cells

“…10) Recently, some reports indicated that GPR56 contributes to tumorigenesis. [12][13][14] Therefore, GPR56 is focused on as a target for anti-cancer drugs. In this research, we generated functional or non-functional monoclonal antibodies against human GPR56 and analyzed the action and signal transduction of GPR56 in human glioma U87-MG cells.…”