Redistribution of DR4 and DR5 in lipid rafts accounts for the sensitivity to TRAIL in NSCLC cells
Redistribution of DR4 and DR5 in lipid rafts accounts for the sensitivity to TRAIL in NSCLC cells
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DR4 和 DR5 在脂筏中的重新分布解释了 NSCLC 细胞对 TRAIL 的敏感性
DOI：
10.3892/ijo.2011.1129
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发表时间：
2011-12-01
影响因子：
5.2
通讯作者：
Xie, Conghua
中科院分区：
文献类型：
--
作者：
Ouyang, Wen;Yang, Chunxu;Xie, Conghua
肿瘤坏死因子相关的凋亡诱导配体(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，大多数已建立的人非小细胞肺癌细胞系对TRAIL部分或完全耐药，从而限制了rhTRAIL及其激动型抗体的临床应用。在本研究中，与TRAIL敏感的H460细胞相比，TRAIL耐药的A549细胞表现出相似的DR5表达水平和更高的DR4表达水平。提示死亡受体的表达水平与TRAIL的敏感性无正相关。然而，用DR4 siRNA转染A549细胞的实验表明，DR4与TRAIL的竞争结合并不影响TRAIL诱导凋亡的能力。相反，进一步的研究发现，DR4和DR5在脂筏中的聚集只发生在TRAIL预处理的H460细胞中。提示TRAIL诱导的DR4和DR5在脂筏中的重新分布与TRAIL敏感的NSCLC H460细胞对TRAIL的敏感性有关，胆固醇封闭剂制霉菌素的干预实验也证实了这一点。
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.