Abstract
Autocrine fibroblast growth factor (FGF) signaling mediates an uncontrollable growth of human gliomas. We investigated the intracellular signaling of FGF on cell survival activity. U251MG human glioma cells were infected with adenovirus vectors expressing dominant negative type I FGF receptor (DNFR), constitutive active Ras (RasL61), or dominant negative Ras (RasN17). DNFR reduced glioma cell accumulation with apoptosis and this reduction was alleviated with exogenous epidermal growth factor (EGF), which can activate Ras independent of FGFR but not with bFGF. RasL61 prevented but RasN17-enhanced DNFR-induced apoptosis. Reportedly, cell survival signaling through Akt was constitutively active in U251MG cells and this effect may be dependent on autocrine signaling and dysfunction of PTEN, a tumor suppressor gene limiting phosphatidylinositol 3-kinase (PI3K) activity. DNFR dose-dependently inhibited Akt activity and this inhibition was recovered by RasL61, whereas RasN17 inhibited Akt activity. Wortmannin (a PI3K inhibitor) inhibited Akt activity and mildly promoted apoptosis. RasL61 prevented the down-regulation of Akt activity and apoptosis induced by wortmannin, but RasN17 plus wortmannin strongly inhibited Akt activity and promoted marked apoptosis. Our data suggested that the cell survival activity of human gliomas is largely dependent on cross-talk between Ras and the PI3K-Akt pathway, and this cross-talk could be a potential target for molecular-based therapeutics.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Apoptosis / genetics
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Autocrine Communication / drug effects
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Autocrine Communication / genetics*
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Brain Neoplasms / drug therapy
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Brain Neoplasms / metabolism*
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Brain Neoplasms / physiopathology
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Cell Division / drug effects
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Cell Division / genetics
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Cell Survival / drug effects
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Cell Survival / genetics*
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Cell Transformation, Neoplastic / drug effects
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Glioma / drug therapy
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Glioma / metabolism*
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Glioma / physiopathology
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Growth Substances / pharmacology
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Humans
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / genetics
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Receptors, Fibroblast Growth Factor / genetics
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Receptors, Fibroblast Growth Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Tumor Cells, Cultured
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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Enzyme Inhibitors
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Growth Substances
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Proto-Oncogene Proteins
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Receptors, Fibroblast Growth Factor
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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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ras Proteins