Abstract
One major obstacle in the clinical application of TRAIL as a cancer therapeutic agent is the acquisition of TRAIL resistance. We found that deficiency of TRADD sensitizes cells to TRAIL-induced apoptosis. Enhanced cell death in TRADD(-/-) MEFs is associated with defective NF-κB activation, indicating that the pro-survival function of TRADD in TRAIL signaling is mediated at least in part via NF-κB activation. Moreover, siRNA knock-down of TRADD in cancer cells sensitizes them to TRAIL-induced apoptosis. Thus, TRADD has a survival role in TRAIL signaling and may be one potential target for overcoming TRAIL resistance in cancer therapy.
Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology*
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Caspase 3 / metabolism
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Caspase 8 / metabolism
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Cell Line, Tumor
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Cells, Cultured
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fibroblasts / cytology
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Fibroblasts / physiology
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Mice
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Mice, Knockout
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NF-kappa B / metabolism*
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction / physiology
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TNF Receptor-Associated Death Domain Protein / genetics
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TNF Receptor-Associated Death Domain Protein / metabolism*
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism*
Substances
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NF-kappa B
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RNA, Small Interfering
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TNF Receptor-Associated Death Domain Protein
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TNF-Related Apoptosis-Inducing Ligand
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Parp1 protein, mouse
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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Caspase 3
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Caspase 8