Contextual Tumor Suppressor Function Of T Cell Death-Associated Gene 8 (TDAG8) In Hematological Malignancies

Abstract

Key points1. TDAG8 (GPR65) gene expression is down-regulated in hematological malignancies.\n\n2. Restoration of TDAG8 gene expression in blood cancer cells suppresses tumor growth and metastasis.\n\nAbstractExtracellular acidosis is a condition found within the tumor microenvironment due to inadequate blood perfusion, hypoxia, and altered tumor cell metabolism. Acidosis has pleiotropic effects on malignant progression; therefore it is essential to understand how acidosis exerts its diverse effects. In this study a bioinformatics analysis revealed the expression of the proton sensing G-protein-coupled receptor TDAG8 is significantly reduced in human blood cancers in comparison to normal blood cells. To understand how TDAG8 functions in hematological malignancies, TDAG8 expression was restored in U937 acute myeloid leukemia cells and other blood cancer cells. It was discovered that severe acidosis, pH 6.4, inhibited U937 cell proliferation while mild acidosis, pH 6.9, stimulated cell proliferation. However, restoring TDAG8 gene expression modulated the U937 cell response to mild extracellular acidosis and physiological pH by reducing cell proliferation. Tumor xenograft experiments further revealed that restoring TDAG8 expression in U937 and Ramos cancer cells reduced tumor growth. It was also shown U937 cells with restored TDAG8 expression attached less to Matrigel, migrated slower toward a chemoattractant, and metastasized less in severe combined immunodeficient mice. These effects correlated with a reduction in c-myc oncogene expression. The mechanistic investigation indicated that G13/RhoA signaling arbitrated the TDAG8-mediated c-myc oncogene repression in response to acidosis. Overall, this study provides compelling data to support the concept that TDAG8 functions as a contextual tumor suppressor in hematological malignancies and sensitizes blood cancer cells to acidotic stress.