Pharmacological targeting of MTHFD2 suppresses NSCLC via the regulation of ILK signaling pathway

Lung cancer is the most common cause of cancer related deaths worldwide with the highest mortality rate. Nonsmall cell lung cancer (NSCLC) accounts for about 85 % of lung cancers. Mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme and is the most differentially expressed metabolic enzyme in various tumors including lung cancer. However, little is known about how MTHFD2 functions in NSCLC. Integrin-linked kinase (ILK) signaling plays key a role in tumor progression including metastasis, proliferation and migration. Here, we show that MTHFD2 inhibition results in suppression of cell growth, migration, invasion and epithelial-mesenchymal transition (EMT) in NSCLC. Microarray analysis suggests that MTHFD2 is positively associated with ILK signaling based on western blotting results. In addition, the phosphorylation of AMPK alpha plays an essential role in MTHFD2 regulation of ILK signaling. Further, the small-molecule compound C18 inhibits MTHFD2 with great efficiency. C18 blocks MTHFD2/ILK signaling pathway and restrains cell growth, migration, invasion, and EMT of NSCLC and induces apoptosis. In brief, our study found that the positive impact of MTHFD2 is mediated via ILK signaling pathway in NSCLC. Thus, blocking MTHFD2 represents a promising therapeutic strategy against NSCLC clinically.

Automated summary

Lung cancer, especially non-small cell lung cancer (NSCLC), is a leading cause of cancer deaths worldwide. The metabolic enzyme MTHFD2, which is highly expressed in various tumors including lung cancer, plays a crucial role in NSCLC through its association with the ILK signaling pathway. Inhibition of MTHFD2 leads to suppression of cell growth, migration, invasion, and EMT, while the small-molecule compound C18 efficiently blocks the MTHFD2/ILK pathway and exhibits potential as a therapeutic strategy against NSCLC.