Proton-sensing Receptor TDAG8 Enhances Cancer Cell Survival through Induction of MCTs in Acidic Environment
Tumor cell survival and metastasis are closely related to the mechanism for a variety of complicated regulating process at the acidic microenvironment. Although several studies have shown that proton sensing receptor TDAG8 might involve in tumor cell survival in acidic condition, but its detailed molecular mechanism is still unclear. So, the study was designed to demonstrate a new mechanism for TDAG8 maintains tumor cell survival and metastasis through induction of MCTs (Monocarboxylate transporters) in acidic condition TDAG8 transgenic lung cancer cells (A549 cells) and hepatocellular ï¼ˆcarcinomaï¼‰cells were used as models in the study. In vivo study was to observe the tumor formation in nude mice after injection of A549-TDAG8 transgenic cells. We found that acidic condition induced the proton-sensing receptor TDAG8 expression and TDAG8 further induced the expression of MCTs and CD147 to improve cancer survival and transfer activity. TDAG8 induced cell survivals and migration were inhibited by α-Cyano-4-hydroxycinnamic acid (CHC), whereas MCT1 and MCT4 expressions were inhibited by H89, TDAG8 induced NF-kB p65 phosphorylation inhibited by H89 and Staurosporine. TDAG8 significantly improved LLC cell survival and increased MCT1, MCT4 and CD147 expression in LLC-TDAG8 cells. Both of tumor tissues formation and MCT1, MCT4, CD147 expression increased in In Vivo experiment. In conclusionï¼ŒTDAG8 induced MCT1/4 expression in acidic condition, were closely associated with tumor cell survival and migration. These findings will provide new evidence to understanding of tumor cell survival and metastasis in acidic environment. Our results indicated that TDAG8 and the signaling pathway involved in MCTs induction by TDAG8 will be potential targets for drug development of tumor treatment.