Efficacy Assessment and Mechanism Exploration of Kruppel‐Like Factor 2‐Targeting Intervention Strategy for Non‐Small Cell Lung Cancer Therapy

Abstract

Non‐small cell lung cancer (NSCLC), the most common type of lung cancer, has the problems such as less sensitivity to chemotherapy and resistance to tyrosine kinase inhibitors. Kruppel‐like factor 2 (KLF2) has been reported to have the potential activities in tumor suppression and immune regulation. The expression level of KLF2 is lower in NSCLC and negatively correlated with the stages of tumor progression and lymph node metastasis. To date, not only no KLF2‐promoting compounds have been developed, but no related studies on its anti‐tumor efficacy in vivo have been verified. Therefore, the purposes of this study were focused on the potential and related mechanisms of KLF2 applied as a targeted molecule for NSCLC therapy. Our data indicated that the intervention of lovastatin markedly up‐regulated protein expression of KLF2 in A549 human non‐small cell lung cancer cells. Moreover, KLF2 siRNA intervention could significant inhibit serum‐induced cell growth in A549 cells. The analysis result of the Ingenuity pathway analysis (IPA) showed that several intracellular molecules, such as AKT, mTOR and FOXO1, maybe the potential upstream regulators to involve in KLF2 expression. Besides, the experimental data also evidenced that lovastatin can suppress activations of AKT and mTOR proteins as well as to reduce protein expression of FOXO1. In summary, these results suggested that intensifying KLF2 expression could apply as a feasible therapeutic strategy to improve NSCLC therapy, and statinoid compounds have potential to be developed as KLF2 activator. In addition, activations or expressions of AKT‐mTOR pathway and FOXO1 may be attributed to suppression of KLF2 in NSCLC cells, such as A549 cells.