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Acidosis decreases c-Myc oncogene expression in human lymphoma cells: a role for the proton-sensing G protein-coupled receptor TDAG8.

Li Z, Dong L, Dean E, Yang LV - Int J Mol Sci (2013)

Bottom Line: The pH-sensing receptor TDAG8 (GPR65) is involved in acidosis-induced c-Myc downregulation.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. yangl@ecu.edu.

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.

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Related in: MedlinePlus

TDAG8 mRNA is decreased by acidosis in U937 cells. U937 cells treated with pH 7.4 or pH 6.4 for three and 6 h were subject to total RNA isolation and real-time RT-PCR using TDAG8-specific primer probes. β-actin was used as an internal control for normalization. TDAG8 expression under the 3-h pH 7.4 treatment was set as one. The data were derived from three biological replicates. Error bars indicate ±SEM. ***p < 0.001.
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f7-ijms-14-20236: TDAG8 mRNA is decreased by acidosis in U937 cells. U937 cells treated with pH 7.4 or pH 6.4 for three and 6 h were subject to total RNA isolation and real-time RT-PCR using TDAG8-specific primer probes. β-actin was used as an internal control for normalization. TDAG8 expression under the 3-h pH 7.4 treatment was set as one. The data were derived from three biological replicates. Error bars indicate ±SEM. ***p < 0.001.

Mentions: Since the tumor microenvironment is characteristically acidic, we investigated whether acidosis might affect TDAG8 expression in U937 lymphoma cells. The real-time RT-PCR results showed that TDAG8 mRNA was reduced by more than 50% under the three-hour pH 6.4 treatment compared to the pH 7.4 treatment (Figure 7). When the treatment was extended to 6 h, the reduction of TDAG8 mRNA by acidic pH was about 70%, whereas the TDAG8 level was moderately increased in the pH 7.4 treatment group (Figure 7). These results suggest that acidosis can downregulate the expression of the TDAG8 pH-sensing receptor, and this may represent a potential mechanism by which TDAG8 mRNA is decreased in lymphomas in comparison to non-tumorous lymphoid tissues, due to acidosis in the tumor microenvironment (Figure 6).


Acidosis decreases c-Myc oncogene expression in human lymphoma cells: a role for the proton-sensing G protein-coupled receptor TDAG8.

Li Z, Dong L, Dean E, Yang LV - Int J Mol Sci (2013)

TDAG8 mRNA is decreased by acidosis in U937 cells. U937 cells treated with pH 7.4 or pH 6.4 for three and 6 h were subject to total RNA isolation and real-time RT-PCR using TDAG8-specific primer probes. β-actin was used as an internal control for normalization. TDAG8 expression under the 3-h pH 7.4 treatment was set as one. The data were derived from three biological replicates. Error bars indicate ±SEM. ***p < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3821613&req=5

f7-ijms-14-20236: TDAG8 mRNA is decreased by acidosis in U937 cells. U937 cells treated with pH 7.4 or pH 6.4 for three and 6 h were subject to total RNA isolation and real-time RT-PCR using TDAG8-specific primer probes. β-actin was used as an internal control for normalization. TDAG8 expression under the 3-h pH 7.4 treatment was set as one. The data were derived from three biological replicates. Error bars indicate ±SEM. ***p < 0.001.
Mentions: Since the tumor microenvironment is characteristically acidic, we investigated whether acidosis might affect TDAG8 expression in U937 lymphoma cells. The real-time RT-PCR results showed that TDAG8 mRNA was reduced by more than 50% under the three-hour pH 6.4 treatment compared to the pH 7.4 treatment (Figure 7). When the treatment was extended to 6 h, the reduction of TDAG8 mRNA by acidic pH was about 70%, whereas the TDAG8 level was moderately increased in the pH 7.4 treatment group (Figure 7). These results suggest that acidosis can downregulate the expression of the TDAG8 pH-sensing receptor, and this may represent a potential mechanism by which TDAG8 mRNA is decreased in lymphomas in comparison to non-tumorous lymphoid tissues, due to acidosis in the tumor microenvironment (Figure 6).

Bottom Line: The pH-sensing receptor TDAG8 (GPR65) is involved in acidosis-induced c-Myc downregulation.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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. yangl@ecu.edu.

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.

Show MeSH
Related in: MedlinePlus