G protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells

Abstract

Dysregulation of G protein-coupled receptors (GPCRs) is known to be involved in the pathogenesis of a variety of diseases, including cancer initiation and progression. Within this family, approximately 140 GPCRs have no known endogenous ligands and these "orphan" GPCRs remain poorly characterized. The orphan GPCR GPR19 was identified and cloned 2 decades ago, but relatively little is known about its physio-pathological relevance. We observed its expression to be elevated in breast cancers and therefore sought to investigate its potential role in breast cancer pathology. In this work, we show that overexpression of GPR19 drives mesenchymal-like breast cancer cells to adopt an epithelial-like phenotype, as demonstrated by the upregulation in E-cadherin expression and changes in functional behavior. We confirm a previous report that a peptide, adropin, is an endogenous ligand for GPR19. We further show that adropin-mediated activation of GPR19 activates the MAPK/ERK1/2 pathway, which is essential for the observed upregulation in E-cadherin and accompanying phenotypic changes. The recapitulation of epithelial characteristics at the secondary tumor sites is now understood to be an essential step in the colonization process. Taken together our work shows for the first time that GPR19 plays a potential role in metastasis by promoting the mesenchymal-epithelial transition (MET) through the ERK/MAPK pathway, thus facilitating colonization of metastatic breast tumor cells.

ERK/MAPK signalling pathway and tumorigenesis (Review)

“…5). Elevated ERK expression has been detected in various human tumours, such as ovarian, colon, breast and lung cancer (85)(86)(87)(88). Denkert et al (89) found that the expression of MAPK phosphatase-1 (MKP-1) in normal ovarian surface epithelium and benign cystadenomas is increased compared to invasive carcinomas and low malignancy potential tumors and borderline tumors.…”

Adropin as A Fat-Burning Hormone with Multiple Functions—Review of a Decade of Research

“…Stein et al found that in rats, adropin suppresses water intake via activation of GPR19 in the brain [5]. Moreover, it was found that adropin modulates E-cadherin expression in breast cancer cells via activation of GPR19 [6]. In addition, another study reported that adropin modulates pyruvate dehydrogenase in cardiac cells in a GPR19-dependent manner [7].…”

“…Several studies found that adropin and its putative receptor GPR19 may be involved in the biology of cancer cells. GPR19 mRNA is high in human breast carcinoma [6]. Furthermore, overexpression of GPR19 in mesenchymal-like breast cancer stimulates E-cadherin expression and promotes the epithelial-like phenotype via the MAPK/ERK1/2 pathway [6].…”

Sphingosine 1–phosphate signaling induces SNAI2 expression to promote cell invasion in breast cancer cells

“…The in vitro invasion assay was performed essentially as previously described by Rao et al (9). Briefly, stably transected MCF7 cells (5 3 10 5 cells per chamber) were plated in DMEM onto the upper compartment of the invasion chamber, and DMEM was added to the lower compartment.…”

“…One alternative approach is to target the pharmacologically tractable membrane receptors transmitting the extracellular signals that regulate intracellular signaling pathways. GPCRs, the largest family of cell surface-signaling molecules, have emerged as critical players in cancer metastasis (8), and our previous work has demonstrated that GPCR expression can affect cancer cell phenotype (9,10). Given the fact that ;50-60% of all current therapeutic agents target GPCRs directly or indirectly (11), targeting GPCR signaling may represent a viable approach for the treatment of breast cancer metastasis.…”