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Int. J. Mol. Sci. 2013, 14(10), 20236-20255; doi:10.3390/ijms141020236
Article

Acidosis Decreases c-Myc Oncogene Expression in Human Lymphoma Cells: A Role for the Proton-Sensing G Protein-Coupled Receptor TDAG8

1
,
1
,
1,†
 and
1,2,3,4,*
1 Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA 2 Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA 3 Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA 4 Lineberger Comprehensive Cancer Center, UNC at Chapel Hill, NC 27599, USA Eric Dean was a summer research student from University of North Carolina at Chapel Hill.
* Author to whom correspondence should be addressed.
Received: 16 August 2013 / Revised: 15 September 2013 / Accepted: 16 September 2013 / Published: 11 October 2013
(This article belongs to the collection G Protein-Coupled Receptor Signaling and Regulation)
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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.
Keywords: acidosis; tumor microenvironment; TDAG8; GPR65; c-Myc acidosis; tumor microenvironment; TDAG8; GPR65; c-Myc
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Li, Z.; Dong, L.; Dean, E.; Yang, L.V. Acidosis Decreases c-Myc Oncogene Expression in Human Lymphoma Cells: A Role for the Proton-Sensing G Protein-Coupled Receptor TDAG8. Int. J. Mol. Sci. 2013, 14, 20236-20255.

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