title: Inhibition of matrix metalloproteinase expression by menatetrenone, a vitamin K2 analogue.
abstract: Vitamin K2 (VK2) has been shown to have a potent anti-tumor effect against several cancer types including hepatocellular carcinoma (HCC), but the mechanisms remain to be elucidated. Matrix metalloproteinase (MMP) plays an important role in the invasion and metastasis of cancer cells, but it is not known whether VK2 regulates the expression of MMPs. Human HCC cell lines were treated with VK2 combined with 12-O-tetradecanoyl phorbol-13 acetate (TPA) and the expression of MMPs was examined by reporter gene assay, RT-PCR and Western blotting. VK2 inhibited the basal and TPA-induced expression of MMP-1, -3 and -7 at the transcriptional, mRNA and protein levels in a dose-dependent manner. VK2 also inhibited the TPA-induced activation of NF-kappaB and AP-1 activity. The inhibitors against NF-kappaB and mitogen-activated protein kinases (MAP kinase) including ERK and JNK pathways suppressed TPA-induced luciferase activity of MMP-1, -3 and -7 promoters. These data suggest that VK2 inhibits MMP expression by suppressing NF-kappaB and MAP kinase activity and might be potentially useful in the treatment of HCC.
authors.affiliation: Department of Internal Medicine, Saga Medical School, Saga University, Saga 849-8501, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ide
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamajima
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Eguchi
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Mizuta
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Kazuma
authors.initials: K
authors.lastname: Fujimoto
authors.forename: Iwata
authors.initials: I
authors.lastname: Ozaki
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology; D020935:MAP Kinase Signaling System; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D024482:Vitamin K 2 / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D011480:Protease Inhibitors; D018808:Transcription Factor AP-1; D024482:Vitamin K 2; C030814:menatetrenone; D011493:Protein Kinase C; D020782:Matrix Metalloproteinases; D013755:Tetradecanoylphorbol Acetate