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Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by BCL-2 and transforming growth factor-beta2.

Abstract

Ezrin belongs to the ezrin-radixin-moesin family proteins, which cross-link actin cytoskeleton and plasma membrane. Malignant glioma cells are paradigmatic for their strong migratory and invasive properties. Here, we report that the expression of dominant-negative ezrins inhibits clonogenicity, migration, and invasiveness of human malignant glioma cells. Furthermore, dominant-negative ezrins block hepatocyte growth factor (HGF)-mediated stimulation of clonogenicity and migration, without altering HGF-induced protein kinase B/Akt and focal adhesion kinase phosphorylation. Glioma cells expressing dominant-negative ezrins exhibit a shift of the BCL-2/BAX rheostat toward apoptosis, reduced alpha(V)beta(3) integrin expression and reduced matrix metalloproteinase (MMP) expression and activity. These changes are associated with a dramatic loss of transforming growth factor beta(2) (TGF-beta(2)) release. Exogenous supplementation of TGF-beta(2) overcomes the inhibitory effects of dominant-negative ezrins on migration and clonogenicity. A neutralizing TGF-beta(2) antibody mimics the effects of dominant-negative ezrins on clonogenicity and migration. Exogenous HGF markedly induces TGF-beta(2) protein levels, and a neutralizing TGF-beta(2) antibody abolishes the HGF-mediated increase in glioma cell motility. Finally, TGF-beta(2) does not modulate BCL-2 or BAX expression, but BCL-2 gene transfer increases the levels of latent and active TGF-beta(2). Intracranial xenografts of U87MG glioma cells transfected with the dominant-negative ezrins in athymic mice grow to significantly smaller volumes, and the median survival of these mice is 50 d compared with 28 d in the control group. These data define a novel pathway for HGF-induced glioma cell migration and invasion, which requires ezrin, changes in the BCL-2/BAX rheostat, and the induction of TGF-beta(2) expression in vitro, and underscore the important role of HGF signaling in vivo.

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  • Authors+Show Affiliations

    ,

    Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Tübingen, Germany. wolfgang.wick@uni-tuebingen.de

    , , , ,

    Source

    MeSH

    Animals
    Apoptosis
    Cell Division
    Cell Movement
    Cytoskeletal Proteins
    Disease Models, Animal
    Genes, Dominant
    Glioma
    Hepatocyte Growth Factor
    Humans
    Mice
    Mice, Nude
    Neoplasm Invasiveness
    Phosphoproteins
    Proto-Oncogene Proteins
    Proto-Oncogene Proteins c-bcl-2
    Rats
    Receptors, Vitronectin
    Survival Rate
    Transfection
    Transforming Growth Factor beta
    Transforming Growth Factor beta2
    Tumor Cells, Cultured
    Tumor Stem Cell Assay
    Xenograft Model Antitumor Assays
    bcl-2-Associated X Protein

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    11331365

    Citation

    Wick, W, et al. "Ezrin-dependent Promotion of Glioma Cell Clonogenicity, Motility, and Invasion Mediated By BCL-2 and Transforming Growth Factor-beta2." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 21, no. 10, 2001, pp. 3360-8.
    Wick W, Grimmel C, Wild-Bode C, et al. Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by BCL-2 and transforming growth factor-beta2. J Neurosci. 2001;21(10):3360-8.
    Wick, W., Grimmel, C., Wild-Bode, C., Platten, M., Arpin, M., & Weller, M. (2001). Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by BCL-2 and transforming growth factor-beta2. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 21(10), pp. 3360-8.
    Wick W, et al. Ezrin-dependent Promotion of Glioma Cell Clonogenicity, Motility, and Invasion Mediated By BCL-2 and Transforming Growth Factor-beta2. J Neurosci. 2001 May 15;21(10):3360-8. PubMed PMID: 11331365.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by BCL-2 and transforming growth factor-beta2. AU - Wick,W, AU - Grimmel,C, AU - Wild-Bode,C, AU - Platten,M, AU - Arpin,M, AU - Weller,M, PY - 2001/5/23/pubmed PY - 2001/6/22/medline PY - 2001/5/23/entrez SP - 3360 EP - 8 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 21 IS - 10 N2 - Ezrin belongs to the ezrin-radixin-moesin family proteins, which cross-link actin cytoskeleton and plasma membrane. Malignant glioma cells are paradigmatic for their strong migratory and invasive properties. Here, we report that the expression of dominant-negative ezrins inhibits clonogenicity, migration, and invasiveness of human malignant glioma cells. Furthermore, dominant-negative ezrins block hepatocyte growth factor (HGF)-mediated stimulation of clonogenicity and migration, without altering HGF-induced protein kinase B/Akt and focal adhesion kinase phosphorylation. Glioma cells expressing dominant-negative ezrins exhibit a shift of the BCL-2/BAX rheostat toward apoptosis, reduced alpha(V)beta(3) integrin expression and reduced matrix metalloproteinase (MMP) expression and activity. These changes are associated with a dramatic loss of transforming growth factor beta(2) (TGF-beta(2)) release. Exogenous supplementation of TGF-beta(2) overcomes the inhibitory effects of dominant-negative ezrins on migration and clonogenicity. A neutralizing TGF-beta(2) antibody mimics the effects of dominant-negative ezrins on clonogenicity and migration. Exogenous HGF markedly induces TGF-beta(2) protein levels, and a neutralizing TGF-beta(2) antibody abolishes the HGF-mediated increase in glioma cell motility. Finally, TGF-beta(2) does not modulate BCL-2 or BAX expression, but BCL-2 gene transfer increases the levels of latent and active TGF-beta(2). Intracranial xenografts of U87MG glioma cells transfected with the dominant-negative ezrins in athymic mice grow to significantly smaller volumes, and the median survival of these mice is 50 d compared with 28 d in the control group. These data define a novel pathway for HGF-induced glioma cell migration and invasion, which requires ezrin, changes in the BCL-2/BAX rheostat, and the induction of TGF-beta(2) expression in vitro, and underscore the important role of HGF signaling in vivo. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/11331365/Ezrin_dependent_promotion_of_glioma_cell_clonogenicity_motility_and_invasion_mediated_by_BCL_2_and_transforming_growth_factor_beta2_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11331365 DB - PRIME DP - Unbound Medicine ER -