title: Plumbagin inhibits TPA-induced MMP-2 and u-PA expressions by reducing binding activities of NF-kappaB and AP-1 via ERK signaling pathway in A549 human lung cancer cells.
abstract: 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 kappaBalpha (IkappaBalpha), and the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-kappaB 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.
authors.affiliation: Department of Pulmonary Medicine, Chi Mei Medical Center, Tainan 710, Taiwan.
authors.forename: Jiunn-Min
authors.initials: JM
authors.lastname: Shieh
authors.forename: Tai-An
authors.initials: TA
authors.lastname: Chiang
authors.forename: Wen-Teng
authors.initials: WT
authors.lastname: Chang
authors.forename: Chang-Hung
authors.initials: CH
authors.lastname: Chao
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Lee
authors.forename: Guan-Yu
authors.initials: GY
authors.lastname: Huang
authors.forename: You-Xin
authors.initials: YX
authors.lastname: Shih
authors.forename: Yuan-Wei
authors.initials: YW
authors.lastname: Shih
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009285:Naphthoquinones / Q000494:pharmacology*; D010766:Phosphorylation; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D009285:Naphthoquinones; D018808:Transcription Factor AP-1; D048052:Mitogen-Activated Protein Kinase 3; D014568:Urokinase-Type Plasminogen Activator; D020778:Matrix Metalloproteinase 2; D013755:Tetradecanoylphorbol Acetate; C014758:plumbagin