Interleukin -1β Promotes Lung Adenocarcinoma Growth and Invasion Through Promoting Glycolysis via p38 Pathway
Qi Tan, Limin Duan, Qi Huang, Wenjuan Chen, Zimo Yang, Jiangbin Chen, Yang Jin
Abstract
BACKGROUND: There is a close relationship among inflammation, glycolysis, and tumors. The IL-1 family includes important inflammatory cytokines, among which IL-1β has been widely studied. In this study, we focused on the effect of IL-1β on glycolysis of lung adenocarcinoma (LUAD) cells in vivo and in vitro and explored its possible mechanisms. METHODS: A bioinformatic database and quantitative real-time PCR were used to analyze the expression of glycolysis-related enzyme genes and their correlations with IL1β in human LUAD samples. The human LUAD cell line A549 and Lewis lung carcinoma LLC cell line were stimulated with IL-1β. In vitro treatment effects, including glycolysis level, migration, and invasion were evaluated with a glucose assay kit, lactate assay kit, Western blotting, wound healing, and the transwell method. We established a mouse model of subcutaneous tumors using LLC cells pretreated with IL-1β and analyzed in vivo treatment effects through positron-emission tomography-computed tomography and staining. Virtual screening and molecular dynamic simulation were used to screen potential inhibitors of IL-1β. RESULTS: Our results showed that IL1β was positively correlated with the expression of glycolysis-related enzyme genes in LUAD. Glycolysis, migration, and invasion significantly increased in A549 and LLC stimulated with IL-1β. In vivo, IL-1β increased growth, mean standard uptake value, and pulmonary tumor metastasis, which were inhibited by the glycolysis inhibitor 2-deoxy-D-glucose and p38-pathway inhibitors. Small molecular compound ZINC14610053 was suggested being a potential inhibitor of IL-1β. CONCLUSION: IL-1β promotes glycolysis of LUAD cells through p38 signaling, further enhancing tumor-cell migration and invasion. These results show that IL-1β links inflammation to glycolysis in LUAD, and targeting IL-1β and the glycolysis pathway may be a potential therapeutic strategy for lung cancer.