Abstract
Glioblastoma is a severe type of primary brain tumor and its invasion is strongly correlated with the secretion of matrix metalloproteinases (MMPs). To investigate a role of PTEN, a tumor suppressor gene, in the regulation of hyaluronic acid (HA)-induced invasion of glioma cells, we examined the secretion of MMP-9 in various glioma cells with or without a functional PTEN gene. The secretion of MMP-9 in glioma cells lacking functional PTEN (U87MG, U251MG, and U373MG) was induced by HA, although not in wildtype (wt)-PTEN-harboring cells (LN229, LN18, and LN428). In addition, stable expression of wt-PTEN into U87MG cells significantly decreased the secretion of HA-induced MMP-9 and basal levels of MMP-2, inhibiting the activation of focal adhesion kinase and extracellular signal-regulated kinase 1/2, whereas the secretion levels of the tissue inhibitor of metalloproteinase-1 and -2 were increased, finally resulting in the inhibition of invasion by HA in vitro. Ectopic expressions of adenoviral (Ad)-wt-PTEN and -lipid phosphatase-deficient (G129E)-PTEN, but not both protein and -lipid phosphatase-deficient (C124S)-PTEN, reduced MMP-9 secretion and invasion by HA. These results were also confirmed by expressions of Ad-wt-PTEN and Ad-G129E-PTEN in other glioblastoma cells lacking functional PTEN, U251MG, and U373MG. These findings strongly suggest the possibility that PTEN may block HA-induced MMP-9 secretion and invasion through its protein phosphatase activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Focal Adhesion Kinase 1
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Focal Adhesion Protein-Tyrosine Kinases
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Glioblastoma / enzymology*
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Humans
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Hyaluronic Acid / antagonists & inhibitors*
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Hyaluronic Acid / pharmacology
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Matrix Metalloproteinase 9 / biosynthesis*
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Matrix Metalloproteinase 9 / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 1 / physiology
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Mitogen-Activated Protein Kinases / physiology
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Neoplasm Invasiveness
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PTEN Phosphohydrolase
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Phosphoprotein Phosphatases / metabolism
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / metabolism
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Phosphoric Monoester Hydrolases / physiology*
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Phosphorylation / drug effects
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Protein-Tyrosine Kinases / metabolism*
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Protein-Tyrosine Kinases / physiology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor Proteins / physiology*
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ras Proteins / metabolism
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ras Proteins / physiology
Substances
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Tumor Suppressor Proteins
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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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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Phosphoprotein Phosphatases
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human
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Matrix Metalloproteinase 9
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ras Proteins