Acacetin inhibits the invasion and migration of human non-small cell lung cancer A549 cells by suppressing the p38α MAPK signaling pathway

Lung cancer is one of the most common malignancies in the world and its metastasis is the major cause of death in cancer patients. Acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound, has anti-peroxidative and anti-inflammatory effects. The effect of acacetin on invasion and migration in human NSCLC A549 cells was investigated. First, the result demonstrated acacetin could exhibit an inhibitory effect on the abilities of the adhesion, morphology/actin cytoskeleton arrangement, invasion, and migration by cell-matrix adhesion assay, immunofluorescence assay, Boyden chamber assay, and wound-healing assay. Molecular data showed that the effect of acacetin in A549 cells might be mediated via sustained inactivation of the phosphorylation of mixed-lineage protein kinase 3 (MLK3), mitogen-activated protein kinase kinases 3/6 (MKK3/6), and p38 alpha MAPK signal involved in the downregulation of the expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (u-PA). Next, acacetin significantly decreased in the phosphorylation and degradation of inhibitor of kappaB alpha (I kappa B alpha), and the nuclear levels of nuclear factor kappa B (NF-kappa B), c-Fos, and c-Jun. Also, the treatment with acacetin to A549 cells also leads to a concentration-dependent inhibition on the binding abilities of NF-kappa B and activator protein-1 (AP-1). Furthermore, the treatment of specific inhibitor for p38 MAPK (SB203580) to A549 cells could cause reduced activities of MMP-2/9 and u-PA. In addition, acacetin significantly decreased the levels of phospho-p38 alpha MAPK, MMP-2/9, and u-PA in p38 alpha-cDNA-transfected cells concomitantly with a marked reduction on cell invasion and migration. Our results revealed the anti-migration and anti-invasion effects of acacetin, which may act as a promising therapeutic agent for the treatment of lung cancer.