Honokiol Inhibits Non-Small Cell Lung Cancer Cell Migration by Targeting PGE2-Mediated Activation of β-Catenin Signaling

Lung cancer remains a leading cause of death due to its metastasis to distant organs. We have examined the effect of honokiol, a bioactive constituent from the Magnolia plant, on human non-small cell lung cancer (NSCLC) cell migration and the molecular mechanisms underlying this effect. Using an in vitro cell migration assay, we found that treatment of A549, H1299, H460 and H226 NSCLC cells with honokiol resulted in inhibition of migration of these cells in a dose-dependent manner, which was associated with a reduction in the levels of cyclooxygenase-2 (COX-2) and prostaglandin E-2 (PGE(2)). Celecoxib, a COX-2 inhibitor, also inhibited cell migration. Honokiol inhibited PGE(2)-enhanced migration of NSCLC cells, inhibited the activation of NF-kappa B/p65, an upstream regulator of COX-2, in A549 and H1299 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-kappa B, also inhibited migration of NSCLC cells. PGE(2) has been shown to activate beta-catenin signaling, which contributes to cancer cell migration. Therefore, we checked the effect of honokiol on beta-catenin signaling. It was observed that treatment of NSCLC cells with honokiol degraded cytosolic beta-catenin, reduced nuclear accumulation of beta-catenin and down-regulated matrix metalloproteinase (MMP)-2 and MMP-9, which are the down-stream targets of beta-catenin and play a crucial role in cancer cell metastasis. Honokiol enhanced: (i) the levels of casein kinase-1 alpha, glycogen synthase kinase-3 beta, and (ii) phosphorylation of beta-catenin on critical residues Ser(45), Ser(33/37) and Thr(41). These events play important roles in degradation or inactivation of beta-catenin. Treatment of celecoxib also reduced nuclear accumulation of beta-catenin in NSCLC cells. FH535, an inhibitor of Wnt/beta-catenin pathway, inhibited PGE(2)-enhanced cell migration of A549 and H1299 cells. These results indicate that honokiol inhibits non-small cell lung cancer cells migration by targeting PGE(2)-mediated activation of delta-catenin signaling.