Abstract
Background:
The cellular form of FLICE-inhibitory protein (cFLIP) blocks death receptor-induced apoptosis and has been implicated in tumour progression. cFLIP interacts with caspase-8, thereby preventing activation of the caspase cascade. In this study we investigated the endogenous expression of cFLIP and caspase-8 in bladder carcinoma cells in relation to their sensitivity to death receptor-ligation.
Materials and methods:
Apoptosis was induced by agonistic anti-CD95 mAbs or recombinant TRAIL and quantified by the TUNEL technique. The relative mRNA expression of cFLIP and caspase-8 was quantified by real-time PCR. Stable expression of cFLIP long (cFLIPL) was obtained by retroviral transduction.
Results:
The relative ratio of cFLIP and caspase-8 was directly correlated to resistance to anti-CD95 or TRAIL-mediated apoptosis. Overexpression of cFLIPL shifted the responsiveness towards resistant status.
Conclusion:
cFLIP is an important determinant of susceptibility to death receptor-induced apoptosis in bladder carcinomas and could function as a prognostic marker for death receptor sensitivity in future immune therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal / pharmacology
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carcinoma / metabolism
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Carcinoma / pathology*
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Carrier Proteins / biosynthesis
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Carrier Proteins / genetics
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Carrier Proteins / physiology*
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Caspase 8
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Caspase 9
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Caspases / biosynthesis
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Caspases / genetics
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Caspases / physiology
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Drug Resistance, Neoplasm
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Enzyme Induction
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Gene Expression Regulation, Neoplastic
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Humans
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In Situ Nick-End Labeling
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Intracellular Signaling Peptides and Proteins*
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Jurkat Cells / metabolism
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Jurkat Cells / pathology
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Membrane Glycoproteins / pharmacology
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / drug effects
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Receptors, Tumor Necrosis Factor / physiology*
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / pharmacology
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Urinary Bladder Neoplasms / metabolism
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Urinary Bladder Neoplasms / pathology*
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fas Receptor / drug effects
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fas Receptor / physiology*
Substances
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Antibodies, Monoclonal
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Apoptosis Regulatory Proteins
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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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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Neoplasm Proteins
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RNA, Messenger
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10A protein, human
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TNFRSF10B protein, human
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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fas Receptor
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CASP8 protein, human
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CASP9 protein, human
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Caspase 8
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Caspase 9
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Caspases