Nuclear localization of Survivin renders HeLa tumor cells more sensitive to apoptosis by induction of p53 and Bax
Nuclear localization of Survivin renders HeLa tumor cells more sensitive to apoptosis by induction of p53 and Bax
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DOI：
10.1016/j.canlet.2006.09.020
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发表时间：
2007-06-08
期刊：
影响因子：
9.7
通讯作者：
Rieber, E. Peter
中科院分区：
文献类型：
--
作者：
Temme, Achim;Rodriguez, Jose A.;Rieber, E. Peter
临床研究表明，凋亡抑制蛋白Survivin在肿瘤细胞核中的表达预示着良好的预后，而胞浆定位的蛋白则导致总生存率下降。因此，Survivin的亚细胞定位可能对其抗凋亡能力很重要。为了解决这个问题，我们研究了Survivin在正常人肺成纤维细胞（NHLFs）和HeLa肿瘤细胞中的定位和功能。早期传代的NHLFs在细胞核中表达Survivin，并且对诱导线粒体凋亡途径的C2神经酰胺高度敏感。相反，传代次数越高的NHLFs使Survivin向胞浆迁移，对C2神经酰胺的耐药性越强，用来普霉素B阻断Survivin向HeLa细胞核的输出可增加对C2神经酰胺的敏感性。此外，转导的HeLa细胞与Survivin融合的核定位信号增强的基础表达水平的p53和Bax和内在凋亡的敏感性增强。这些发现表明，一个主要的核定位的Survivin增加的敏感性促凋亡刺激，而核输出使Survivin能够履行其抑制凋亡的功能。将Survivin保持在肿瘤细胞核中的治疗干预可能会改善癌症治疗。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
Clinical studies have shown that nuclear expression of the inhibitor of apoptosis protein Survivin in tumor cells predicted a favorable prognosis whereas cytosolic-localized protein caused a decreased overall survival. Therefore Survivin's subcellular localization may be important for its anti-apoptotic capacity. To address this question, we investigated localization and function of Survivin in normal human lung fibroblasts (NHLFs) and HeLa tumor cells. NHLFs of early passages expressed Survivin in the nucleus and were highly sensitive to C2 ceramide, which induces the mitochondrial apoptotic pathway. In contrast, NHLFs at higher passages relocated Survivin to the cytosol and became more resistant to C2 ceramide.Blocking nuclear export of Survivin by leptomycin B in HeLa cells increased susceptibility to C2 ceramide. In addition, transduction of HeLa cells with Survivin fused to a nuclear localization signal augmented basal expression levels of p53 and Bax and enhanced sensitivity for intrinsic apoptosis. Those findings suggest that a predominant nuclear localization of Survivin increases the sensitivity for pro-apoptotic stimuli, whereas nuclear export enables Survivin to fulfill its inhibitor of apoptosis function. A therapeutic intervention which holds Survivin in the nucleus of tumor cells might improve cancer therapy. (c) 2006 Elsevier Ireland Ltd. All rights reserved.