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

Mototsugu Oya, Masafumi Ohtsubo, Atsushi Takayanagi, Masaaki Tachibana, Nobuyoshi Shimizu, Masaru Murai

Research output: Contribution to journalArticlepeer-review

134 Citations (Scopus)

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-κB is a key molecule underlying the TRAIL-resistant mechanism in renal cell carcinoma (RCC) cell lines. We observed that NF-κB is constitutively activated in resistant cell lines. Forced expression of antisense cDNA of IκBα, a specific inhibitor of NF-κB, in TRAIL-sensitive cell lines with a low NF-κB activity result in constitutive activation of NF-κB and resistance to TRAIL-induced apoptosis. Adenoviral expression of a stable form of IκBα 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-κB activity and TRAIL-resistant RCC with constitutively activated NF-κB. In the former group TRAIL can be a treatment option, while in the latter group a molecular approach targeting NF-κB appears to be a promising therapy.

Original languageEnglish
Pages (from-to)3888-3896
Number of pages9
JournalOncogene
Volume20
Issue number29
DOIs
Publication statusPublished - 2001 Jun 28

Keywords

  • Apoptosis
  • IκBα
  • NF-κB
  • Renal cell carcinoma
  • TRAIL

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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