Acacetin Inhibits TPA-Induced MMP-2 and u-PA Expressions of Human Lung Cancer Cells Through Inactivating JNK Signaling Pathway and Reducing Binding Activities of NF-kappa B and AP-1

Acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound, has antiperoxidative and antiinflammatory effects. The effect of acacetin on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMPs and u-PA expressions in human lung cancer A549 cells was investigated. First, the result demonstrated acacetin could inhibit TPA-induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and Boyden chamber assay. Data also showed acacetin could inhibit phosphorylation of c-Jun N-terminal-kinase 1 and 2 (JNK1/2) involved in the down-regulating protein expressions and transcriptions of matrix metalloproteinase-2 (MMP-2) and urokinase-type plasminogen activator (u-PA) induced by TPA. Next, acacetin also strongly inhibited TPA-stimulated the nuclear levels of nuclear factor kappa B (NF-kappa B), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-kappa B and activator protein-1 (AP-1) by acacetin treatment was further observed. Further, the treatment of specific inhibitor for INK (SP600125) to A549 cells could inhibit TPA-induced MMP-2 and u-PA expressions along with an inhibition on cell invasion and migration. Taken together, these results suggest the antimetastatic effects of acacetin on the TPA-induced A549 cells might be by reducing MMP-2 and u-PA expressions through inhibiting phosphorylation of INK and reducing NF-kappa B and AP-1 binding activities.