Abstract
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 E2 (PGE2). Celecoxib, a COX-2 inhibitor, also inhibited cell migration. Honokiol inhibited PGE2-enhanced migration of NSCLC cells, inhibited the activation of NF-κB/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-κB, also inhibited migration of NSCLC cells. PGE2 has been shown to activate β-catenin signaling, which contributes to cancer cell migration. Therefore, we checked the effect of honokiol on β-catenin signaling. It was observed that treatment of NSCLC cells with honokiol degraded cytosolic β-catenin, reduced nuclear accumulation of β-catenin and down-regulated matrix metalloproteinase (MMP)-2 and MMP-9, which are the down-stream targets of β-catenin and play a crucial role in cancer cell metastasis. Honokiol enhanced: (i) the levels of casein kinase-1α, glycogen synthase kinase-3β, and (ii) phosphorylation of β-catenin on critical residues Ser45, Ser33/37 and Thr41. These events play important roles in degradation or inactivation of β-catenin. Treatment of celecoxib also reduced nuclear accumulation of β-catenin in NSCLC cells. FH535, an inhibitor of Wnt/β-catenin pathway, inhibited PGE2-enhanced cell migration of A549 and H1299 cells. These results indicate that honokiol inhibits non-small cell lung cancer cells migration by targeting PGE2-mediated activation of β-catenin signaling.
Highlights
Lung cancer is responsible for more deaths in the US each year than breast, colon and prostate cancers combined, and has a tremendous impact on human health and health care expenditures [1]
The antibodies specific for b-catenin were purchased from R&D Biosystems (Minneapolis, MN), celecoxib, prostaglandin E2 (PGE2) were from Sigma Chemical Company, an enzyme immunoassay kit for PGE2 analysis was obtained from Cayman Chemicals (Ann Arbor, MI), while antibodies for phospho b-catenin, CK1a, GSK-3b, matrix metalloproteinase (MMP)-2, MMP-9, COX-2, NF-kB, IKKa, IkBa and b-actin were obtained from Cell Signaling Technology (Beverly, MA)
As we have found that treatment of Non-small-cell lung cancer (NSCLC) cells with honokiol inhibits the levels of PGE2 and inhibits PGE2enhanced migration of lung cancer cells, we have further determined whether inhibition of NSCLC cell migration by honokiol is associated with the suppression of b-catenin signaling
Summary
Lung cancer is responsible for more deaths in the US each year than breast, colon and prostate cancers combined, and has a tremendous impact on human health and health care expenditures [1]. Cyclooxygenase-2 (COX-2) is frequently constitutively up-regulated in different human malignancies, including lung cancers [6,7,8,9,10]. Among the PGs, PGE2 is considered the most effective metabolite or inflammatory mediator that is thought to play a central role in cancer growth, progression, invasion and metastasis. Smith et al [12] have shown that ultraviolet radiation-induced COX-2 expression and PGE2 production results in enhanced activation of b-catenin signaling. There are reports which suggest that COX2/PGE2/b-catenin axis or link is associated with the lung cancer metastasis [13]. Lung cancer is a highly malignant cancer with a potent capacity to metastasize distantly and a major cause of cancerrelated deaths, an approach that reduces its metastatic ability may facilitate the development of an effective strategy for its treatment and/or prevention
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