Abstract
The capacity of glial tumor cells to migrate and diffusely infiltrate normal brain compromises surgical eradication of the disease. Identification of genes associated with invasion may offer novel strategies for anti-invasive therapies. The gene for TXsyn, an enzyme of the arachidonic acid pathway, has been identified by differential mRNA display as being overexpressed in a glioma cell line selected for migration. In this study TXsyn mRNA expression was found in a large panel of glioma cell lines but not in a strain of human astrocytes. Immunohistochemistry demonstrated TXsyn in the parenchyma of glial tumors and in reactive astrocytes, whereas it could not be detected in quiescent astrocytes and oligodendroglia of normal brain. Glioma cell lines showed a wide range of thromboxane B2 formation, the relative expression of which correlated with migration rates of these cells. Migration was effectively blocked by specific inhibitors of TXsyn, such as furegrelate and dazmegrel. Other TXsyn inhibitors and cyclooxygenase inhibitors were less effective. Treatment with specific inhibitors also resulted in a decrease of intercellular adhesion in glioma cells. These data indicate that TXsyn plays a crucial role in the signal transduction of migration in glial tumors and may offer a novel strategy for anti-invasive therapies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Arachidonic Acids / metabolism
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Aspirin / analogs & derivatives*
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Aspirin / pharmacology
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Astrocytes / drug effects
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Astrocytes / enzymology
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Astrocytes / physiology
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Benzofurans / pharmacology
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Brain Neoplasms / enzymology
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Brain Neoplasms / genetics
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Brain Neoplasms / pathology*
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Cell Adhesion / drug effects
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Cell Movement / physiology
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Enzyme Induction
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Enzyme Inhibitors / pharmacology
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GTP-Binding Proteins / metabolism
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Glioma / enzymology
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Glioma / genetics
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Glioma / pathology*
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Humans
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Imidazoles / pharmacology
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Indomethacin / pharmacology
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Lysine / analogs & derivatives*
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Lysine / pharmacology
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Models, Biological
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / physiology*
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / enzymology
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Neoplastic Stem Cells / physiology*
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Oligodendroglia / drug effects
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Oligodendroglia / enzymology
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Oligodendroglia / physiology
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Pentanoic Acids / pharmacology
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Phenotype
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Pyridines / pharmacology
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RNA, Messenger / biosynthesis
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RNA, Neoplasm / biosynthesis
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Signal Transduction
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Thromboxane B2 / biosynthesis
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Thromboxane-A Synthase / antagonists & inhibitors
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Thromboxane-A Synthase / biosynthesis
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Thromboxane-A Synthase / genetics
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Thromboxane-A Synthase / physiology*
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / enzymology
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Tumor Cells, Cultured / physiology
Substances
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Arachidonic Acids
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Benzofurans
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Enzyme Inhibitors
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Imidazoles
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Neoplasm Proteins
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Pentanoic Acids
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Pyridines
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RNA, Messenger
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RNA, Neoplasm
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dazoxiben
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dazmegrel
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Thromboxane B2
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imidazole
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GTP-Binding Proteins
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Thromboxane-A Synthase
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Lysine
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furegrelate
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ridogrel
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Aspirin
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acetylsalicylic acid lysinate
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Indomethacin