Oya M, Ohtsubo M, Takayanagi A, Tachibana M, Shimizu N, Murai M
Department of Urology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan.
Oncogene. 2001 Jun 28;20(29):3888-96. doi: 10.1038/sj.onc.1204525.
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.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）因其能特异性诱导癌细胞凋亡而不诱导正常细胞凋亡，备受关注。这种现象的解释如下：癌细胞主要表达死亡受体，而正常细胞表达诱饵受体。然而，最近的报道表明，一些癌细胞系尽管不存在诱饵受体且存在死亡受体，但对TRAIL诱导的凋亡具有抗性。这提示存在一种抑制因子。我们在此表明，核因子κB（NF-κB）是肾细胞癌（RCC）细胞系中TRAIL抗性机制的关键分子。我们观察到，NF-κB在抗性细胞系中持续激活。在NF-κB活性较低的TRAIL敏感细胞系中，强制表达NF-κB的特异性抑制剂IkappaBalpha的反义cDNA，会导致NF-κB的持续激活以及对TRAIL诱导凋亡的抗性。在TRAIL抗性细胞系中，腺病毒表达稳定形式的IkappaBalpha可诱导凋亡。这些数据表明，RCC可分为两个亚组：NF-κB活性较低的TRAIL敏感型RCC和NF-κB持续激活的TRAIL抗性型RCC。在前一组中，TRAIL可以作为一种治疗选择，而在后一组中，针对NF-κB的分子方法似乎是一种有前景的治疗方法。
