Selective inhibition of MMP-9 gene expression by mangiferin in PMA-stimulated human astroglioma cells: Involvement of PI3K/Akt and MAPK signaling pathways

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• 作者：Ji-Sun Jung^a ; Kangsik Jung^b ; Dong-Hyun Kim^b ; Hee-Sun Kim^a ; ^{hskimp@ewha.ac.kr}
• 关键词：AP ; activator protein ; EMSA ; electrophoretic mobility shift assay ; ERK ; extracellular signal-regulated kinase ; JNK ; c-Jun N-terminal kinase ; MAPK ; mitogen-activated protein kinase ; MgF ; mangiferin ; MMP ; matrix metalloproteinase ; NF-魏B ; nuclear factor-魏B
• 刊名：Pharmacological Research
• 出版年：2012
• 期刊代码：54_10436618
• 类别：pha
• 出版时间：July, 2012
• 卷：66
• 期：1
• 页码：95-103
• 文件大小：1188 K

摘要

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-魏B 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.