The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor

Abstract

Tumors often are associated with a low extracellular pH, which induces a variety of cellular events. However, the mechanisms by which tumor cells recognize and react to the acidic environment have not been fully elucidated. T-cell death-associated gene 8 (TDAG8) is an extracellular pH-sensing G protein-coupled receptor that is overexpressed in various tumors and tumor cell lines. In this report, we show that TDAG8 on the surface of tumor cells facilitates tumor development by sensing the acidic environment. Overexpression of TDAG8 in mouse Lewis lung carcinoma (LLC) cells enhanced tumor development in animal models and rendered LLC cells resistant to acidic culture conditions by increasing activation of protein kinase A and extracellular signal-regulated kinase in vitro. Moreover, shRNA-mediated knockdown of endogenous TDAG8 in NCI-H460 human non-small cell lung cancer cells reduced cell survival in an acidic environment in vitro as well as tumor development in vivo. Microarray analyses of tumorcontaining lung tissues of mice injected with TDAG8-expressing LLC cells revealed up-regulation of genes related to cell growth and glycolysis. These results support the hypothesis that TDAG8 enhances tumor development by promoting adaptation to the acidic environment to enhance cell survival/proliferation. TDAG8 may represent a therapeutic target for arresting tumor growth.Lewis lung carcinoma cells | orphan receptor | tumor-induced acidity | tumorigenesis

Acidosis Promotes Bcl-2 Family-mediated Evasion of Apoptosis

“…7D). This follows from previous work by other groups demonstrating that pH-activated GPR65 signals through the G␣ s /cAMP pathway and additionally through ERK1/2 phosphorylation (22,23,25). The ablation of both downstream signals indicates that our knockdown protocol effectively blunts the activity of GPR65.…”

“…The activation of GPR65 only occurs below pH 7.4 and reaches maximal activity between pH 6.2 and 6.8, in line with in vivo tumor pH (22,23). Additionally, it was recently revealed that the ability of GPR65 to promote tumor formation requires its acid-sensing capabilities (25). Whereas these reports provide evidence for the importance of GPR65 in cancer, exactly how the receptor exerts its oncogenic function is unknown.…”

Adaptation by the collecting duct to an exogenous acid load is blunted by deletion of the proton-sensing receptor GPR4

“…Our interest in elucidating a role for an acid sensor in the kidney has been based on the relatively high expression of the proton-sensing receptor GPR4 in the kidney and the responses of other members of the proton-sensing family of GPCR to a decrease in pH in various tissues [e.g., OGR1 in bone (36,37,55) and lung], TDAG8 in lung carcinoma (50), and GPR4 in blood vessels (106). We found that the deletion of GPR4 impairs net acid excretion in the kidney, and therefore a spontaneous non-gap metabolic acidosis develops (88).…”

Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

“…99 Another group demonstrated in NCI-H460 human non-small cell lung cancer cells that GPR65 promotes cancer cell survival in an acidic microenvironment. 100 Conversely, a recent study showed that GPR65 inhibited c-Myc oncogene expression in human lymphoma cells. 101 Furthermore, GPR65 messenger ribonucleic acid expression was reduced by more than 50% in a variety of human lymphoma samples when compared to normal lymphoid tissues, therefore implying GPR65 has a tumor suppressor function in lymphoma.…”