Abstract
Emodin, an inhibitor of protein tyrosine kinase, possesses antiviral, immunosuppressive, anti-inflammatory and anticancer effects. In the present study, we investigated the effect of emodin on the hyaluronic acid (HA)-induced invasion of human glioma cells. Emodin significantly inhibited the HA-induced invasion through a Matrigel coated chamber, secretion of matrix metalloproteinase (MMP)-2, and HA-induced secretion of MMP-9 in glioma cells. To investigate the possible mechanisms involved in these events, we performed Western blot analysis using phospho-specific antibodies, and found that emodin inhibited phosphorylation of focal adhesion kinase (FAK), extracellular regulated protein kinase (ERK) 1/2 and Akt/PKB; emodin also suppressed the transcriptional activity of two transcription factors, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB), in glioma cells. In addition, oral administration of emodin suppressed in vivo MMP secretion by glioma tumors in nude mice. Taken together, our results indicate that emodin can effectively inhibit HA-induced MMP secretion and invasion of glioma through inhibition of FAK, ERK1/2 and Akt/PKB activation and partial inhibition of AP-1 and NF-kappaB transcriptional activities. Consequently, these results provide important insights into emodin as an anti-invasive agent for the therapy of human glioma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Line, Tumor
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Cell Movement / drug effects
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Dose-Response Relationship, Drug
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Emodin / pharmacology*
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Emodin / therapeutic use
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Enzyme Inhibitors / pharmacology
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Glioma / drug therapy*
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Glioma / metabolism
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Glioma / pathology
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Humans
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Hyaluronic Acid / pharmacology*
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / metabolism
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Neoplasm Invasiveness
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Reverse Transcriptase Polymerase Chain Reaction
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Time Factors
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Transcription Factor AP-1 / metabolism
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Xenograft Model Antitumor Assays / methods
Substances
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Enzyme Inhibitors
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NF-kappa B
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Proto-Oncogene Proteins
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Transcription Factor AP-1
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Hyaluronic Acid
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Protein-Tyrosine Kinases
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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PTK2 protein, human
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Ptk2 protein, mouse
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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Matrix Metalloproteinase 2
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Matrix Metalloproteinase 9
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Emodin