Rapamycin decreases survivin expression to induce NSCLC cell apoptosis under hypoxia through inhibiting HIF-1α induction
Rapamycin decreases survivin expression to induce NSCLC cell apoptosis under hypoxia through inhibiting HIF-1α induction
复制标题
DOI：
10.1007/s11033-011-0724-3
复制
发表时间：
2012-01-01
影响因子：
2.8
通讯作者：
Ni, Jian
中科院分区：
文献类型：
--
作者：
Chen, Bin;Yuping, Sun;Ni, Jian
Survivin是凋亡抑制蛋白家族的一员，在多种肿瘤中过表达，在抑制细胞凋亡中起重要作用。了解细胞凋亡的分子事件可能为开发针对非小细胞肺癌（NSCLC）的新型治疗药物提供信息。本研究使用了三种人NSCLC细胞系NCI-H1299、SK-MES-1和NCI-H460。分析细胞凋亡、Survivin mRNA和蛋白表达在常氧和缺氧、雷帕霉素处理前后的变化。此外，进一步应用siRNA和ChIP检测来证实低氧诱导因子1（HIF-1）α在低氧条件下对雷帕霉素诱导的NSCLC细胞凋亡过程中Survivin表达的调节作用。雷帕霉素处理导致缺氧条件下NSCLC细胞凋亡显著增加。我们首次证明雷帕霉素抑制低氧诱导的NSCLC细胞系中生存素的表达。我们进一步证明HIF-1 α参与了缺氧诱导的生存素表达，雷帕霉素通过增强其降解抑制缺氧诱导的HIF-1 α表达。以上结果共同表明，雷帕霉素抑制缺氧条件下HIF-1 α诱导的生存素表达，从而诱导NSCLC凋亡。
Survivin is a member of the inhibitor of apoptosis protein family that is overexpressed in various tumors and is important in restricting apoptosis. Understanding the molecular events of apoptosis may provide information for developing novel therapeutic agents targeting non-small cell lung cancer (NSCLCs). This study used three human NSCLC cell lines, NCI-H1299, SK-MES-1, and NCI-H460. Changes in apoptosis, the mRNA and protein expression of survivin under normoxia and hypoxia, with or without rapamycin treatment were analyzed. In addition, siRNA and ChIP assay were further applied to demonstrate the role of hypoxia-inducible factor 1 (HIF-1)alpha in regulating survivin expression regulation under hypoxia during rapamycin induced NSCLC cell apoptosis. Treatment with rapamycin resulted in significantly increased NSCLC cells apoptosis under hypoxia. We demonstrated for the first time that rapamycin inhibited hypoxia-induced survivin expression in NSCLC cell lines. We further demonstrated that HIF-1 alpha participated in hypoxia-induced survivin expression, and that rapamycin inhibited hypoxia-induced HIF-1 alpha expression by enhancing its degradation. The results above collectively showed that rapamycin inhibits HIF-1 alpha-induced survivin expression under hypoxia to induce NSCLC apoptosis.