Abstract
TRAIL has gained much attention for its specific induction of apoptosis in cancer cells but not in normal cells. This phenomenon has been explained thus: that cancer cells dominantly express death receptors while normal cells express decoy receptors. However, recent reports have shown that some cancer cell lines are resistant to TRAIL-induced apoptosis despite the absence of decoy receptors and the presence of death receptors. This suggested the existance of an inhibitory factor. We herein showed that NF-kappaB is a key molecule underlying the TRAIL-resistant mechanism in renal cell carcinoma (RCC) cell lines. We observed that NF-kappaB is constitutively activated in resistant cell lines. Forced expression of antisense cDNA of IkappaBalpha, a specific inhibitor of NF-kappaB, in TRAIL-sensitive cell lines with a low NF-kappaB activity result in constitutive activation of NF-kappaB and resistance to TRAIL-induced apoptosis. Adenoviral expression of a stable form of IkappaBalpha in the TRAIL-resistant cell lines induced apoptosis. These data suggest that RCC can be classified into two subsets: TRAIL-sensitive RCC with a low NF-kappaB activity and TRAIL-resistant RCC with constitutively activated NF-kappaB. In the former group TRAIL can be a treatment option, while in the latter group a molecular approach targeting NF-kappaB appears to be a promising therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / metabolism*
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Antineoplastic Agents / pharmacology
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Apoptosis Regulatory Proteins
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Apoptosis*
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Carcinoma, Renal Cell / drug therapy
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Carcinoma, Renal Cell / metabolism*
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Caspase 8
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Caspase 9
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Caspases / genetics
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Caspases / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Enzyme Activation
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GPI-Linked Proteins
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Humans
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I-kappa B Proteins*
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Kidney Neoplasms / drug therapy
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Kidney Neoplasms / metabolism*
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Ligands
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / pharmacology
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor, Member 10c
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured
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Tumor Necrosis Factor Decoy Receptors
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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DNA-Binding Proteins
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GPI-Linked Proteins
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I-kappa B Proteins
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Ligands
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Membrane Glycoproteins
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NF-kappa B
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NFKBIA protein, human
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Member 10c
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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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TNFRSF10C protein, human
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TNFSF10 protein, human
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Tumor Necrosis Factor Decoy Receptors
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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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