| Metabolic reprogramming is considered one of the hallmarks of cancer.Due to the complexity and heterogeneity,different tumor tissues have different microenvironments and metabolic phenotypes.Cell metabolism is a complex and dynamic system.The studies of the changes and interrelationship of multiple metabolic pathways can help to understand the relationship between the microenvironment and tumor metabolic reprogramming.Glutamine is necessary nitrogen source for body biosynthesis.The transport,decomposition and metabolism of glutamine play an important role in the occurrence and development of tumors,but few studies have focused on the changes of nucleotide metabolism in cancer.Due to the energy supply mode of cells in brain tissues bases on glucose,amino acids and ketone bodies,and blood-brain barrier and Warburg effect,brain tumor often exists in low-glucose and acidic microenvironments.This study focuses on the glutamine metabolism and nucleotide metabolism in gliomas under the low-glucose and acidic microenvironment.This study will further reveal the relationship between microenvironment and metabolic reprogramming of glioma.It is great meaningful to understand the role of glutamine metabolism and nucleotide metabolism in the occurrence and development of tumors and mutual coordination.In this study,we found that key enzymes in glutamine metabolism and nucleotide synthesis pathways were high expressed in glioma through bioinformatics analysis.The high expression of ASCT2 and PPAT is related to the poor prognosis of patients.The immunoblotting and tissue microarray results of clinical samples of tumors also showed that ASCT2 and PPAT were highly expressed in glioma tissues,and the positive rate of PPAT protein expression increased with the increase of tumor malignancy.Cytological experiments also showed that knocking down PPAT can significantly inhibit the proliferation of T98 G cells.Those results suggest that glutamine metabolism and nucleotide synthesis are enhanced in glioma tissues,and PPAT can promote the proliferation of glioma cell.In order to study the influence of the microenvironment on the metabolic reprogramming of glioma,we simulated the microenvironment of glioma by changing the culture conditions of T98 G cells.We cultured T98 G cells in low-glucose or lowglucose and acidic medium,and studied the effects of microenvironment on cell proliferation,cell cycle and cellular metabolic pathways.The results showed that compared with normal cultured cells,T98 G cells grew more slowly under low-glucose conditions,S-phase cells were significantly reduced,and G2-phase cells increased.Cellular glutamine metabolism and nucleotide synthesis pathway were up-regulated,glycolysis and pentose phosphate pathway were down-regulated.Under low-glucose and acidic condition,growth of cells was close to the cells under normal culture condition,the proportion of S-phase cells was higher than that cell under low-glucose culture condition.And cellular glycolysis was down-regulated,pentose phosphate pathway,glutamine metabolism and nucleotide synthesis pathway were up-regulated.At the same time,the expression of c-Myc was detected to increase significantly,and the m RNA and protein expression of its downstream regulatory proteins ASCT2,GLS and PPAT were also up-regulated.The results showed that c-Myc regulated glutamine metabolism and nucleotide synthesis in glioma cell,and promoted cell proliferation to adapt to the lowglucose and acidic microenvironment.Our research found that c-Myc maybe regulated pentose phosphate pathway,glutamine metabolism and nucleotide synthesis in glioma cell under low-glucose and acidic microenvironment,and promoted glioma cell proliferation.This study lays the great significance for understanding the role of glutamine and nucleotide metabolism in the occurrence and development of glioma,and also provides new ideas for the research of the tumorigenesis molecular mechanism and treatment of glioma. |
PDF Full Text Request