Licorice isoliquiritigenin dampens angiogenic activity via inhibition of MAPK-responsive signaling pathways leading to induction of matrix metalloproteinases.
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.
Kang
Sang-Wook
SW
Department of Food and Nutrition and Korean Institute of Nutrition, Hallym University, Chuncheon, Kangwon-do, 200-702, South Korea.
Choi
Jung-Suk
JS
Choi
Yean-Jung
YJ
Bae
Ji-Young
JY
Li
Jing
J
Kim
Dong Shoo
DS
Kim
Jung-Lye
JL
Shin
Seung-Yong
SY
Lee
Yong-Jin
YJ
Kwun
In-Sook
IS
Kang
Young-Hee
YH
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
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