title: Selective inhibition of MMP-9 gene expression by mangiferin in PMA-stimulated human astroglioma cells: involvement of PI3K/Akt and MAPK signaling pathways.
abstract: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases which play a key role in invasion, migration, and angiogenesis of astrogliomas and other malignant tumors. Thus, controlling MMPs has been considered an important therapeutic strategy for prevention and/or treatment of gliomas. However, most MMP inhibitors developed so far are broad spectrum inhibitors; thus, it is necessary to develop a selective MMP inhibitor to minimize potential side effects. In the present study, we found that mangiferin, a glucosylxanthone isolated from Anemarrhena asphodeloides, specifically inhibited MMP-9 gene expression in phorbol myristate acetate (PMA)-stimulated human astroglioma U87MG, U373MG, and CRT-MG cells. However, it did not affect other MMPs, such as MMP-1, -2, -3, and -14. Mangiferin suppressed MMP-9 expression at the promoter, mRNA, and protein levels and additionally inhibited MMP-9 enzymatic activity. The Matrigel-invasion assay showed that mangiferin suppresses the in vitro invasiveness of glioma cells, which appears to be correlated with mangiferin-mediated MMP-9 inhibition. Further mechanistic studies demonstrated that mangiferin inhibits the binding of NF-κB and AP-1 to the MMP-9 promoter and suppresses the PMA-induced phosphorylation of Akt and MAP kinases, which are upstream signaling molecules in MMP-9 expression. Thus, the specific inhibition of MMP-9 by mangiferin may provide a valuable pharmacological tool for treatment of gliomas.
authors.affiliation: Department of Molecular Medicine, Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, Republic of Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Jung
authors.forename: Kangsik
authors.initials: K
authors.lastname: Jung
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001254:Astrocytoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001665:Binding Sites; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011480:Protease Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D011480:Protease Inhibitors; D018808:Transcription Factor AP-1; D044004:Xanthones; C013592:mangiferin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate