Metabolic Alteration Regulates Stemness And Radioresistance Of Tumor Cells

Radiation resistance of tumor cells is determined by properties of tumor cells(internal factors)and surrounding microenvironment(external factors).The unique properties of tumor cells include stemness and DNA damage repair capacity.Tumor microenvironment consists of tumor stromal cells,tumor matrix and the acidic environment,et al.As a hallmark of tumor,the upregualted glutamine metabolism plays an important role in enhancing tumorigenicity and malignant transformation.The tumor stem-like cells were a subpopulation of tumor cells highly resistant to radiation.However,the role of glutamine metabolism in tumor resistance to radiation is not clear.Glutamic pyruvate transaminase(GPT)catalyzes the reversible transamination of glutamate and pyruvate to alanine and α-ketoglutarate(α-KG).The homologous isomer GPT1 is a biomarker used clinically in liver diseases.We reported that the expression of type II GPT(GPT2)was markedly elevated in breast cancer and correlated with the pathological grades of breast cancers.GPT2 overexpression increased the subpopulation of breast cancer stem cells in vitro and promoted tumorigenesis in mice.Ectopic expression of GPT2 reduced α-KG level in cells leading to the inhibition of proline hydroxylase 2(PHD2)activities and promoting HIF1α stability.Accumulation of HIF1α,resulting from GPT2-α-KG-PHD2 axial,constitutively activated sonic hedgehog(Shh)signaling pathway,increasing the subpopulation of breast cancer stem-like cells.Cancer-associated fibroblasts(CAFs)are the major component of the tumor matrix,and closely related to the growth and metastasis of malignant tumors.In previous studies,our data have demonstrated that glycose metabolism was reprogrammed in CAFs and CAFs enhanced the resistance of tumor cells to radiation therapy.Our current results revealed that CAFs in the tumor microenvironment enhanced the radioresistance by upregulating insulin-like growth factor 1(IGF1).We found that the increased α-KG promoted IGF1 expression in CAFs by activating histone demethylases,KDM2 A,KDM5B and KDM1 A,of which activities are regulated by α-KG.Further studies have identified that KDM2 A and KDM5 B associated each other and bound to the different promoter region of IGF1,sbusequentially upregulated IGF1 expression and secretion,eventually enhanced the radiotherapeutic resistance of tumor cells.In conclusion,we demonstrated that GPT2 increased stemness of tumor cells by decreasing the level of α-KG in breast cancer cells;and α-KG promoted IGF1 expression in CAF,which enhanced radioresistance of colon cancer cells.In brief,our study demonstrated that the metabolic alteration in tumor enhanced the radioresistance of tumor cells,and paved a way for radiosensitization of cancer.