Plumbagin inhibits TPA-induced MMP-2 and u-PA expressions by reducing binding activities of NF-κB and AP-1 via ERK signaling pathway in A549 human lung cancer cells
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This study first investigates the anti-metastatic effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMPs and u-PA expressions in human lung cancer cells, A549. First, the result demonstrated plumbagin could inhibit TPA induced the abilities of the adhesion, invasion, and migration by cell–matrix adhesion assay and Boyden chamber assay. Data also showed plumbagin could inhibit the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) involved in the down-regulating enzyme activities, protein and messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and urokinase-type plasminogen activator (u-PA) induced by TPA. Next, plumbagin also strongly inhibited TPA-induced phosphorylation and degradation of inhibitor of kappaBα (IκBα), and the nuclear levels of nuclear factor kappa B (NF-κB), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-κB and activator protein-1 (AP-1) by plumbagin treatment was further observed. Further, the treatment of specific inhibitor for ERK (U0126) to A549 cells could inhibit TPA-induced MMP-2 and u-PA expressions along with an inhibition on cell invasion and migration. Presented data reveals that plumbagin is a novel, effective, anti-metastatic agent that functions by down-regulating MMP-2 and u-PA gene expressions.
KeywordsPlumbagin Invasion Migration ERK1/2 MMP-2 u-PA
Urokinase-type plasminogen activator
Extracellular signaling-regulating kinase
c-Jun N-terminal kinase/stress-activated protein kinase
- p38 MAPK
p38 Mitogen-activated protein kinase
Phosphoinositide 3-kinase/protein kinase B
Nuclear factor kappa B
Inhibitor of NF-κB
This work was supported by the grant from the Subsidized Project of the Chung Hwa University, Tainan, Taiwan (97-HT-08011).
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