Department of Radiation and Medical Oncology, Zhongnan Hospital, Wuhan University, 169 Donghu Road, Wuchang District, Wuhan 430071, P.R. China.
Int J Oncol. 2011 Dec;39(6):1577-86. doi: 10.3892/ijo.2011.1129. Epub 2011 Jul 18.
The selective toxicity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against tumor cells makes it a potential targeted drug for treating non-small cell lung carcinomas (NSCLC). However, the majority of established human NSCLC cell lines are either partially or completely resistant to TRAIL, resulting in the limitation for clinical use of rhTRAIL and its agonistic antibodies. In this study, compared to TRAIL-sensitive H460 cell line, TRAIL-resistant A549 cell line showed a similar expression level of DR5 and a higer expression level of DR4. It indicates that there is no positive correlation between the expression levels of death receptors and sensitivity to TRAIL. However, tests on A549 cells with DR4 siRNA transfection revealed that DR4-competitive binding to TRAIL could not affect the capacity of TRAIL in inducing apoptosis. Instead, further studies found that the aggregation of DR4 and DR5 in lipid rafts only occured in H460 cells with TRAIL pretreatment. It suggested that the TRAIL-induced redistribution of DR4 and DR5 in lipid rafts contributed to the sensitivity to TRAIL in TRAIL-sensitive NSCLC H460 cell line, which was also confirmed by intervention tests of the cholesterol-sequestering agent nystatin.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）对肿瘤细胞的选择性毒性使其成为治疗非小细胞肺癌（NSCLC）的潜在靶向药物。然而，大多数已建立的人 NSCLC 细胞系对 TRAIL 部分或完全耐药，导致 rhTRAIL 及其激动性抗体的临床应用受限。在这项研究中，与 TRAIL 敏感的 H460 细胞系相比，TRAIL 耐药的 A549 细胞系显示出相似的 DR5 表达水平和更高的 DR4 表达水平。这表明死亡受体的表达水平与对 TRAIL 的敏感性之间没有正相关关系。然而，用 DR4 siRNA 转染 A549 细胞的测试表明，DR4 与 TRAIL 的竞争性结合不能影响 TRAIL 诱导凋亡的能力。相反，进一步的研究发现，只有在 TRAIL 预处理的 H460 细胞中，DR4 和 DR5 在脂筏中的聚集才会发生。这表明 TRAIL 诱导的 DR4 和 DR5 在脂筏中的重新分布有助于 TRAIL 敏感的 NSCLC H460 细胞系对 TRAIL 的敏感性，这也通过胆固醇隔离剂制霉菌素的干预测试得到了证实。
