Carbon nanotubes induce apoptosis resistance of human lung epithelial cells through FLICE-inhibitory protein.
Carbon nanotubes induce apoptosis resistance of human lung epithelial cells through FLICE-inhibitory protein.
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碳纳米管通过FLICE抑制蛋白诱导人肺上皮细胞凋亡抵抗。
DOI：
10.1093/toxsci/kfu251
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Rojanasakul,Yon
中科院分区：
文献类型：
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作者：
Pongrakhananon,Varisa;Luanpitpong,Sudjit;Stueckle,ToddA;Wang,Liying;Nimmannit,Ubonthip;Rojanasakul,Yon
长期暴露于单壁碳纳米管（SWCNT）已被报道诱导人肺上皮细胞的凋亡抵抗。由于细胞凋亡抵抗是肿瘤转化和癌症发展的基础，我们评估了暴露的肺细胞的凋亡抵抗特性，以了解发病机制。通过内源性（抗霉素A和CDDP）或外源性（FasL和TNF-α）途径，用已知的细胞凋亡诱导剂处理传代对照和SWCNT转化的人肺上皮细胞，并通过DNA片段化、膜联蛋白-V表达和半胱天冬酶活化试验分析细胞凋亡。采用全基因组芯片分析凋亡基因信号网络。SWCNT转化的细胞表现出与细胞FLICE抑制蛋白（c-FLIP）过表达相关的死亡受体途径缺陷。敲低或化学抑制c-FLIP废除SWCNT转化细胞的凋亡抗性。全基因组表达特征分析证实了这些发现。这项研究首次证明了碳纳米管诱导的缺陷性死亡受体途径以及c-FLIP在该过程中的作用。
Chronic exposure to single-walled carbon nanotubes (SWCNT) has been reported to induce apoptosis resistance of human lung epithelial cells. As resistance to apoptosis is a foundation of neoplastic transformation and cancer development, we evaluated the apoptosis resistance characteristic of the exposed lung cells to understand the pathogenesis mechanism. Passage control and SWCNT-transformed human lung epithelial cells were treated with known inducers of apoptosis via the intrinsic (antimycin A and CDDP) or extrinsic (FasL and TNF-α) pathway and analyzed for apoptosis by DNA fragmentation, annexin-V expression, and caspase activation assays. Whole-genome microarray was performed to aid the analysis of apoptotic gene signaling network. The SWCNT-transformed cells exhibited defective death receptor pathway in association with cellular FLICE-inhibitory protein (c-FLIP) overexpression. Knockdown or chemical inhibition of c-FLIP abrogated the apoptosis resistance of SWCNT-transformed cells. Whole-genome expression signature analysis confirmed these findings. This study is the first to demonstrate carbon nanotube-induced defective death receptor pathway and the role of c-FLIP in the process.