Crosstalk Of MTOR/PKM2 And STAT3/c-Myc Signaling Pathways Regulate The Energy Metabolism And Acidic Microenvironment Of Gastric Cancer

Background:The Warburg effect refers to the fact that cancer cells produce lactic acid by consuming a large amount of glucose,which results in a marked increase in glycolysis,which occurs even when oxygen is abundant.The occurrence of this condition led to the production of large amounts of lactic acid by the cells and further secretion outside the cells,which further aggravated the acidic microenvironment of the tumor and increased the invasiveness of the tumor cells.In clinical work,drug resistance also greatly increased.c-Myc is an important member of the Myc gene family and participates in the development of various tumors.It plays an important role in regulating tumor energy metabolism,and it can regulate glycolysis of tumors and promote the Warburg effect of tumors.PKM2 is highly expressed in tumor tissues and embryonic tissues.Studies have confirmed that mTOR/PKM2 signaling pathway can affect tumor glycolysis levels and STAT3/c-Myc affects tumor glutamate metabolism.Our previous studies have found that inhibition of mTOR/PKM2 signaling pathways can affect the biological behavior and glycolysis of gastric cancer cells.Objective:Our study aimed to improve the malignant biological behavior by controlling the energy metabolism of gastric cancer through the mTOR/PKM2 and STAT3/c-Myc signaling pathways through a series of in vitro experiments.Methods:Human gastric cancer AGS and HGC-27 cells were treated with PKM2 and c-Myc lentivirus,and the effects of knockdown PKM2 and/or c-Myc were analyzed on cell proliferation,cell apoptosis,the ability of cell migration and growth signaling pathway in vitro.The expressions of PKM2,c-Myc,LDHA,STAT3,P-STAT3,GLUT-1 gene were identified by quantitative real-time polymerase chain reaction(Q-PCR)and western blotting.Lactic acid kits and glucose kits were used to detect extracellular lactate and glucose levels.Result:Our experimental results showed that the expression of PKM2 and c-Myc was significantly increased in human gastric cancer cells.Knockdown of c-Myc can inhibit the expression of c-Myc mRNA and protein in gastric cancer AGS and HGC-27 cells,thereby further inhibiting the proliferation,migration,colony formation and glycolysis of gastric cancer cells.Knocking down both PKM2 and c-Myc was more effective in suppressing gastric cancer cells than knocking out PKM2 or c-Myc alone.At the same time,our study also found that there is a correlation between mTOR/PKM2 and STAT3/c-Myc signaling pathways,and they regulate each other to jointly regulate gastric cancer energy metabolism.Conclusion:C-Myc might be considered as a potential therapeutic target for gastric cancer.The combination of PKM2 and c-Myc can better inhibit the malignant biological behavior of gastric cancer,and the mechanism may be related to the interaction between the two pathways.