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

Ji Sun Jung, Kangsik Jung, Dong Hyun Kim, Hee Sun Kim

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57 Scopus citations

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.

Original languageEnglish
Pages (from-to)95-103
Number of pages9
JournalPharmacological Research
Volume66
Issue number1
DOIs
StatePublished - Jul 2012

Bibliographical note

Funding Information:
This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) ( 2010-0029354 ).

Keywords

  • Gene regulation
  • Glioma invasion
  • Mangiferin
  • MAP kinases
  • Matrix metalloproteinase-9
  • PI3K/Akt

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