Abstract
Many malignant glioma cells express death receptors for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), yet some of these cells are resistant to TRAIL. Here, we examined signaling events in TRAIL-induced apoptosis and searched for therapeutic agents that could overcome TRAIL resistance in glioma cells. TRAIL induced apoptosis through death receptor 5 (DR5) and was mediated by caspase-8-initiated extrinsic and intrinsic mitochondrial pathways in sensitive glioma cell lines. TRAIL also triggered apoptosis in resistant glioma cell lines through the same pathways, but only if the cells were pretreated with chemotherapeutic agents, cisplatin, camptothecin and etoposide. Previous studies suggested that this was due to an increase in DR5 expression in wild-type TP53 cells, but this mechanism did not account for cells with mutant TP53. Here, we show that a more general effect of these agents is to downregulate caspase-8 inhibitor c-FLIP(S) (the short form of cellular Fas-associated death domain-fike interleukin-1-converting enzyme-inhibitory protein) and up-regulate Bak, a pro-apoptotic Bcl-2 family member, independently of cell's TP53 status. Furthermore, we showed that TRAIL alone or in combination with chemotherapeutic agents, induced apoptosis in primary tumor cultures from patients with malignant gliomas, reinforcing the potential of TRAIL as an effective therapeutic agent for malignant gliomas.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / physiology*
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Apoptosis Inducing Factor
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Apoptosis Regulatory Proteins
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Blotting, Northern
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Blotting, Western
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Brain Neoplasms / pathology
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / pharmacology
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Caspases / metabolism
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Caspases / pharmacology
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Cytochromes c
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Dose-Response Relationship, Drug
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Drug Interactions
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Enzyme Inhibitors / pharmacology
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Flavoproteins / metabolism
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Flow Cytometry
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Glioma / pathology
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Humans
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Intracellular Signaling Peptides and Proteins*
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Membrane Glycoproteins / physiology*
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Membrane Proteins / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Proteins / metabolism
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Receptors, Tumor Necrosis Factor / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Subcellular Fractions / drug effects
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Subcellular Fractions / metabolism
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TNF-Related Apoptosis-Inducing Ligand
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Temperature
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Time Factors
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / physiology*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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X-Linked Inhibitor of Apoptosis Protein
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bcl-2 Homologous Antagonist-Killer Protein
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rho GTP-Binding Proteins / metabolism
Substances
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AIFM1 protein, human
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Antineoplastic Agents
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Apoptosis Inducing Factor
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Apoptosis Regulatory Proteins
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BAK1 protein, human
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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Enzyme Inhibitors
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Flavoproteins
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Membrane Proteins
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Proteins
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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Tumor Suppressor Protein p53
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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bcl-2 Homologous Antagonist-Killer Protein
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Cytochromes c
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Caspases
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rho GTP-Binding Proteins