title: Licorice isoliquiritigenin dampens angiogenic activity via inhibition of MAPK-responsive signaling pathways leading to induction of matrix metalloproteinases.
abstract: The aberrant expression of matrix metalloproteinases (MMPs) has been implicated in matrix degradation leading to angiogenesis. This study examined the inhibitory effects of isoliquiritigenin (ISL) on phorbol myristate acetate (PMA)-induced MMP production and its tissue inhibitor of MMP (TIMP) in endothelial cells. No induction of either necrotic or apoptotic cell death was observed in response to a treatment with ISL at <or=25 microM. ISL dose-dependently suppressed PMA-induced expression and activity of MMP-2 and membrane type 1-MMP at >or=1 microM while diminishing the elevated MMP-2 transcript level. In addition, ISL inhibited PMA-triggered migration and tube formation in a dose-dependent manner. ISL further increased the TIMP production up-regulated by PMA with a biphasic effect on TIMP-2 expression. This study further attempted to investigate whether a c-Jun N-terminal kinase (JNK)- or p38 mitogen-activated protein kinase (MAPK)-responsive mechanism was responsible for the MMP production and whether ISL disturbed these signaling pathways. PMA stimulated signaling of JNK and p38 MAPK, which was dampened by >or=10 microM ISL. These results demonstrate that ISL blocked JNK- or p38 MAPK-responsive pathways leading to direct MMP activation of PMA-exposed endothelial cells. Therefore, the ISL inhibition of MMP may boost a therapeutic efficacy during angiogenesis.
authors.affiliation: Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702, South Korea.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
authors.forename: Jung-Suk
authors.initials: JS
authors.lastname: Choi
authors.forename: Yean-Jung
authors.initials: YJ
authors.lastname: Choi
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Bae
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Dong Shoo
authors.initials: DS
authors.lastname: Kim
authors.forename: Jung-Lye
authors.initials: JL
authors.lastname: Kim
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Shin
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Lee
authors.forename: In-Sook
authors.initials: IS
authors.lastname: Kwun
authors.forename: Young-Hee
authors.initials: YH
authors.lastname: Kang
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000166:cytology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047188:Chalcones; D019715:Tissue Inhibitor of Metalloproteinase-1; D016159:Tumor Suppressor Protein p53; D019716:Tissue Inhibitor of Metalloproteinase-2; C040920:isoliquiritigenin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases; D013755:Tetradecanoylphorbol Acetate