N6-methyladenosine methyltransferase METTL3 facilitates the aerobic glycolysis of non-small cell lung cancer cells by activating the PI3K/AKT/mTOR pathway

Non-small cell lung Cancer (NSCLC) is a malignancy with poor outcomes. METTL3 has been demonstrated to facilitate aerobic glycolysis for malignancies. We aimed to explore how METTL3 regulates aerobic glycolysis in NSCLC. METTL3 and PIK3CB expressions in NSCLC tissues, and the associations between METTL3 and Akt, as well as METTL3 and mTOR were analyzed by public databases. After NSCLC cells with METTL3 knockdown or overexpression were successfully established, the malignant behaviors of the cells were evaluated. Subsequently, cellular aerobic glycolysis was detected by measuring glucose consumption, lactate production, ATP/ADP ratio and the expressions of GLUT1, HK2, PKM2 and LDHA proteins. Furthermore, PI3K, Akt and mTOR phosphorylation of the cells was detected. Finally, METTL3 silenced cells were exposed to 740Y-P (a PI3K Activator) and 2-Deoxy-d-glucose (a glycolysis inhibitor) to further investigate the mechanisms of METTL3 on NSCLC. METTL3 and PI3KCB were highly expressed, and METTL3 expression positively correlated with Akt and mTOR expressions in NSCLC clinical samples. METTL3 knockdown suppressed NSCLC cellular viability, migration and invasion, but induced Apoptosis. Furthermore, METTL3 knockdown decreased above aerobic glycolysis-related indicators, and suppressed PI3K, Akt and mTOR phosphorylation. Conversely, METTL3 overexpression produced opposite effects. Notably, the suppression of METTL3 silencing on NSCLC cellular viability, migration and aerobic glycolysis were reserved by 740Y-P, and the roles of 740Y-P on METTL3-silenced cells were further counteracted by 2-Deoxy-d-glucose. METTL3 may facilitate the aerobic glycolysis of NSCLC cells by activating the PI3K/Akt/mTOR pathway, indicating that the METTL3-mediated PI3K/Akt/mTOR axis is an underlying therapeutic target for NSCLC.

Aerobic glycolysis; METTL3; Malignant behaviors; Non-small cell lung cancer cells; PI3K/AKT/mTOR pathway.