Tumor Microenvironment Induces MCT1/MCT4 Expression To Regulate Glioma Metabolism

Tumor cells supply energy by glycolysis even under aerobic conditions,the phenomenon known as the"Warburg effect."Since the rapid proliferation of tumor cells requires the intake of a large amount of glucose for cells use,glucose is hydrolyzed to produce a large amount of lactic acid,so tumor cells are often accompanied by an acidic microenvironment.The utilization of glucose,the blood-brain barrier and the rapid proliferation of tumor cells lead to a hypoxic,acidic and nutrient-deficient microenvironment.Studies have found that lactic acid in tumor tissues can be reused by surrounding cells through the transport of the monocarboxylate transporter MCT1/MCT4,the phenomenon known as metabolic symbiosis.But does the microenvironment of glioma induce MCT1/MCT4 expression?The role of MCT1/MCT4 in glioma proliferation and its regulatory mechanism is not clear.Studying this issue is of great significance for the pathogenesis and clinical treatment of glioma.In this study,glioma cells T98G and U251 were used as materials to study the effects of glucose deficiency and lactic acid culture conditions on glioma cell growth and lactic acid metabolism.The study found that low glucose culture conditions inhibited the growth of glioma cells,and lactic acid culture conditions promoted the growth of glioma cells,and ATP maintained a high level.The effect of lactic acid on promoting cell proliferation and maintaining cell energy levels is more pronounced in the presence of insufficient glucose and the presence of lactic acid.It is indicated that glioma cells can use lactic acid as an energy source to maintain cell proliferation and growth.The expressions of lactic acid metabolism-related proteins in different culture conditions were detected.The expressions of MCT1,MCT4 and HIF-1 a were significantly increased in glioma cells under lactic acid culture conditions,while the expressions of MCT1,MCT4 and GLUT1 were decreased in low glucose medium..It indicated that lactic acid could induce the increase of MCT1/MCT4 expression,promote the transport and utilization of lactic acid in glioma,and strengthen the oxidative phosphorylation pathway.After inhibiting the expression of MCT1,the growth of glioma cells was inhibited,the level of ATP decreased,and the expression of cellular oxidative phosphorylation-related proteins(HIF-1 a,ND1)was down-regulated.Similar results were obtained with the treatment of cells with the inhibitor of MCT1,7ACC2.At the same time,we constructed a nude mouse model of T98G cells in vitro.The volume and size of tumors were significantly lower than that of the control after treatment with inhibitor 7ACC2.The expression of MCT1 and MCT4 was significantly down-regulated in tumor tissues,and the expression of NDUFA9 and ND1 also decreased.It indicates that the down-regulation of MCT1/MCT4 can effectively block the transport of lactic acid and inhibit the growth of tumor.It can be seen that MCT1 plays an important role in the proliferation of glioma cells.In the clinical samples of glioma,we also detected that the expression levels of HIF-1 a,MCT4,MCT1 and LDH in glioma tissues were significantly higher than those in adjacent tissues,and the glioma core area and adjacent areas were typical.Metabolic symbiosis.The informatics analysis of the tumor database also showed that the high expression of HIF-1 a,MCT4 and MCT1 was associated with poor prognosis of patients,and the expression of HIF-1 a was positively correlated with the expression of MCT4,MCT1 and MYC.The above results show that lactic acid metabolism is widely present in gliomas.MCT1 plays an important role in promoting the transport and reuse of lactic acid in different regions of tumor tissues,and MCT1 is expected to be a target molecule for clinical treatment of glioma.At the same time,it is suggested that acidic and low glucose microenvironment may induce HIF-1 a to regulate the expression of MCT1 to promote tumor cell proliferation.This study lays a foundation for further exploring the molecular mechanism of lactic acid metabolism in brain tumors,and provides new ideas of clinical treatment strategies for glioma.