Tan Qi, Duan Limin, Huang Qi, Chen Wenjuan, Yang Zimo, Chen Jiangbin, Jin Yang
Department of Respiratory and Critical Care Medicine, NHC Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, People's Republic of China.
J Inflamm Res. 2021 Dec 2;14:6491-6509. doi: 10.2147/JIR.S319433. eCollection 2021.
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.
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.
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.
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.
炎症、糖酵解与肿瘤之间存在密切关系。白细胞介素-1（IL-1）家族包含重要的炎性细胞因子，其中IL-1β已得到广泛研究。在本研究中，我们聚焦于IL-1β在体内和体外对肺腺癌（LUAD）细胞糖酵解的影响，并探讨其可能的机制。
利用生物信息学数据库和定量实时聚合酶链反应（PCR）分析人LUAD样本中糖酵解相关酶基因的表达及其与IL1β的相关性。用IL-1β刺激人LUAD细胞系A549和Lewis肺癌LLC细胞系。通过葡萄糖检测试剂盒、乳酸检测试剂盒、蛋白质免疫印迹法、伤口愈合实验和Transwell法评估体外治疗效果，包括糖酵解水平、迁移和侵袭。我们用经IL-1β预处理的LLC细胞建立皮下肿瘤小鼠模型，并通过正电子发射断层扫描-计算机断层扫描和染色分析体内治疗效果。利用虚拟筛选和分子动力学模拟筛选IL-1β的潜在抑制剂。
我们的结果显示，IL1β与LUAD中糖酵解相关酶基因的表达呈正相关。用IL-1β刺激的A549和LLC细胞中，糖酵解、迁移和侵袭显著增加。在体内，IL-1β增加了肿瘤生长、平均标准摄取值和肺肿瘤转移，糖酵解抑制剂2-脱氧-D-葡萄糖和p38通路抑制剂可抑制这些作用。小分子化合物ZINC14610053被认为是IL-1β的潜在抑制剂。
IL-1β通过p38信号通路促进LUAD细胞的糖酵解，进一步增强肿瘤细胞的迁移和侵袭。这些结果表明，IL-1β在LUAD中将炎症与糖酵解联系起来，靶向IL-1β和糖酵解途径可能是肺癌的一种潜在治疗策略。
