The Function And Molecular Mechanism Of 4EBP1 In Mediating Extracellular Glucose Sensing In Non-small Cell Lung Cancer

Metabolic reprogramming is one of the ten characteristics of tumor,which plays an important role in the occurrence and development of tumor.Aerobic glycolysis(Warburg effect)is one of the main characteristics of tumor metabolic reprogramming.It means that tumor cells take a lot of glucose even under aerobic conditions,and convert it into lactic acid through glycolysis rather than oxidative phosphorylation,thus providing tumor cells with a lot of energy and precursors for the synthesis of biomacromolecules.At present,scientists have done a lot of research on the regulatory mechanism of tumor glycolysis,and many important breakthroughs has been made.However,little is known about how tumor cells sense the extracellular glucose level and start the corresponding signaling pathway to affect cell survival.4EBP1 is known as a translational repressor to regulate cell proliferation and survival by controlling translation initiation in nucleus,but the role of 4EBP1 in the cytoplasm remains unknown.Here,we described that 4EBP1 was dephosphorylated by PTPMT1 under glucose starvation conditions,which prevented 4EBP1 from ubiquitin-mediated proteasomal degradation by HERC5.Further studies demonstrated that the dephosphorylated 4EBP1 translocated into cytoplasm and interacted with STAT3 by competing with ERK,leading to the reduced phosphorylation of STAT3 at Tyr705 and inactivation of STAT3,thus resulting in apoptosis under glucose withdrawal conditions.Moreover,4EBP1 knockdown increased the tumor volume and weight in xenograft models by inhibiting apoptosis induced by glucose deficiency.These results discover a new role of 4EBP1 that acts as an essential signaling molecular that linking extracellular glucose sensing to cell survival.