Constitutive activation of nuclear factor-kappaB prevents TRAIL-induced apoptosis in renal cancer cells.
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.
Oya
M
M
Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. moto-oya@med.keio.ac.jp
Ohtsubo
M
M
Takayanagi
A
A
Tachibana
M
M
Shimizu
N
N
Murai
M
M
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D058851:GPI-Linked Proteins; D006801:Humans; D020672:I-kappa B Proteins; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D058851:GPI-Linked Proteins; D020672:I-kappa B Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases