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

1email, 1email, 1,†email and 1,2,3,4,* email
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; in revised form: 15 September 2013 / Accepted: 16 September 2013 / Published: 11 October 2013
(This article belongs to the collection G Protein-Coupled Receptor Signaling and Regulation)
PDF Full-text Download PDF Full-Text [1585 KB, uploaded 11 October 2013 16:44 CEST]
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

Supplementary Files

Article Statistics

Load and display the download statistics.

Citations to this Article

Cite This Article

MDPI and ACS Style

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.

AMA Style

Li Z, Dong L, Dean E, Yang LV. Acidosis Decreases c-Myc Oncogene Expression in Human Lymphoma Cells: A Role for the Proton-Sensing G Protein-Coupled Receptor TDAG8. International Journal of Molecular Sciences. 2013; 14(10):20236-20255.

Chicago/Turabian Style

Li, Zhigang; Dong, Lixue; Dean, Eric; Yang, Li V. 2013. "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. 14, no. 10: 20236-20255.

Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert