Expression Profiles and Impact of Proton-sensitive G Protein-Coupled Receptors (GPCRs) on Cell Proliferation and Migration in Tumor Growth and Wound Healing

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Solid tumors and wounds are among the most important cost drivers in our healthcare systems. Dysregulation of pH is a feature of both tumor growth and tissue repair. In tumors,microenvironmental changes, like in lactate metabolism, lead to altered transmembranous pH-gradients (with decreased extra- and increased intracellular pH-values: pHe < pHi) and vice versa. In wounds, barrier disruption results in extensive variations in pHe on the wound surface. It is known that altered extracellular proton concentrations have a major impact on cell turnover and migration as well as on the metabolic activity of cells involved in tumor spread and wound closure. The proton-sensing G protein-coupled receptors (GPCRs) GPR4 (GPR19), GPR65 (TDAG8, T-cell death-associated gene 8), GPR68 (OGR1, ovarian cancer GPCR 1) and GPR132 (G2A, G2 accumulation protein) are activated via a decrease in pHe and transduce this signal to molecular intracellular pathways. Based on the current knowledge, we speculate on the role of proton-sensing GPCRs in wound healing and on their potential as mechanistic linkers of tumor growth and tissue repair, both processes being highly dependent on cell proliferation and migration. The expression of these GPCRs in normal adult cells (keratinocytes, fibroblasts) and tumor cells (melanoma, squamous cell carcinoma) will be studied comprehensively in cell culture and histology for the first time. Additionally, we will study the impact of pHe on cell proliferation and migration after selective knockout of the different proton-sensitive GPCRs (via CRISPR/Cas, alternatively siRNA). The results will provide new insights on the role of proton-sensitive GPCRs in tumor growth and wound healing, and they will be important for the use of drugs modifying tumor pH, potentially also for drugs directly acting on proton-sensitive GPCRs.