Constitutive activation of nuclear factor-kappaB prevents TRAIL-induced apoptosis in renal cancer cells

Oncogene. 2001 Jun 28;20(29):3888-96. doi: 10.1038/sj.onc.1204525.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacology
  • Apoptosis Regulatory Proteins
  • Apoptosis*
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / metabolism*
  • Caspase 8
  • Caspase 9
  • Caspases / genetics
  • Caspases / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • GPI-Linked Proteins
  • Humans
  • I-kappa B Proteins*
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / metabolism*
  • Ligands
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / pharmacology
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor, Member 10c
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • GPI-Linked Proteins
  • I-kappa B Proteins
  • Ligands
  • Membrane Glycoproteins
  • NF-kappa B
  • NFKBIA protein, human
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Member 10c
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • TNFRSF10C protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor Decoy Receptors
  • Tumor Necrosis Factor-alpha
  • NF-KappaB Inhibitor alpha
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 8
  • Caspase 9
  • Caspases