Constitutive activation of nuclear factor-κB 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-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.