title: Acidosis decreases c-Myc oncogene expression in human lymphoma cells: a role for the proton-sensing G protein-coupled receptor TDAG8.
abstract: Acidosis is a biochemical hallmark of the tumor microenvironment. Here, we report that acute acidosis decreases c-Myc oncogene expression in U937 human lymphoma cells. The level of c-Myc transcripts, but not mRNA or protein stability, contributes to c-Myc protein reduction under acidosis. The pH-sensing receptor TDAG8 (GPR65) is involved in acidosis-induced c-Myc downregulation. TDAG8 is expressed in U937 lymphoma cells, and the overexpression or knockdown of TDAG8 further decreases or partially rescues c-Myc expression, respectively. Acidic pH alone is insufficient to reduce c-Myc expression, as it does not decrease c-Myc in H1299 lung cancer cells expressing very low levels of pH-sensing G protein-coupled receptors (GPCRs). Instead, c-Myc is slightly increased by acidosis in H1299 cells, but this increase is completely inhibited by ectopic overexpression of TDAG8. Interestingly, TDAG8 expression is decreased by more than 50% in human lymphoma samples in comparison to non-tumorous lymph nodes and spleens, suggesting a potential tumor suppressor function of TDAG8 in lymphoma. Collectively, our results identify a novel mechanism of c-Myc regulation by acidosis in the tumor microenvironment and indicate that modulation of TDAG8 and related pH-sensing receptor pathways may be exploited as a new approach to inhibit Myc expression.
authors.affiliation: Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. yangl@ecu.edu.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Li
authors.forename: Lixue
authors.initials: L
authors.lastname: Dong
authors.forename: Eric
authors.initials: E
authors.lastname: Dean
authors.forename: Li V
authors.initials: LV
authors.lastname: Yang
mesh_terms: D000138:Acidosis / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019169:Jurkat Cells; D008198:Lymph Nodes / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D013154:Spleen / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics; D020298:U937 Cells
chemical_list: C513334:GPR65 protein, human; D043562:Receptors, G-Protein-Coupled