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.
Highlights
The c-Myc oncogene is a member of the Myc family, which includes L-Myc, N-Myc, S-Myc and B-Myc [1,2,3]
Because it has been reported that TDAG8 is the major proton sensor in lymphocytes and the proton-sensing function of G2A is controversial [39], we focused on TDAG8 to test whether it is involved in acidosis-induced c-Myc downregulation
To further elucidate the connection between TDAG8 and acidosis-induced c-Myc downregulation, we identified a human lung cancer cell line, H1299, in which c-Myc expression was not decreased by acidic pH (Figure 5A)
Summary
The c-Myc oncogene is a member of the Myc family, which includes L-Myc, N-Myc, S-Myc and B-Myc [1,2,3]. TDAG8 is highly expressed in lymphoid tissues and lymphoma and leukemia cell lines [43,44,45,46,47]. Both tumor-promoting and tumor-suppressing activities of TDAG8 have been reported. In WEHI7.2 and CEM-C7 T-cell lymphoma cell lines, TDAG8 is activated by acidosis to promote the evasion of apoptosis under glutamine. TDAG8 has been reported as a tumor suppressor, which promotes glucocorticoid-induced apoptosis in murine lymphoma cells and thymocytes [45,47]. We demonstrate that acidosis and TDAG8 suppresses the expression of the c-Myc oncogene in lymphoma cells. Our results show that TDAG8 expression is significantly decreased in human lymphoma samples in comparison to normal lymphoid tissues, suggesting a potential tumor suppressor function of TDAG8 in lymphoma
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