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
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)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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
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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.

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