The canonical NF-κB pathway differentially protects normal and human tumor cells from ROS-induced DNA damage.
The canonical NF-κB pathway differentially protects normal and human tumor cells from ROS-induced DNA damage.
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DOI：
10.1016/j.cellsig.2012.06.010
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发表时间：
2012-11
影响因子：
4.8
通讯作者：
Kolettas E
中科院分区：
文献类型：
--
作者：
Sfikas A;Batsi C;Tselikou E;Vartholomatos G;Monokrousos N;Pappas P;Christoforidis S;Tzavaras T;Kanavaros P;Gorgoulis VG;Marcu KB;Kolettas E
DNA损伤反应根据刺激强度和p53-p21Cip1/Waf1轴的激活程度而引起衰老或凋亡；但在正常细胞和人类癌细胞中，NF-κB信号对这些不同结果的功能影响仍然知之甚少。我们研究了正常人肺成纤维细胞和A549人肺癌上皮细胞的核因子-κB依赖的效应和ROS介导的DDR结果的机制。为了激活DDR，不同剂量的H_2O_2诱导ROS的积累。ROS诱导引起两种人细胞的G2-M期细胞周期停滞。然而，ROS介导的DDR最终在不同的终点达到顶峰，HDFS经历了过早衰老，A549癌细胞屈从于凋亡。H_2O_2介导的ROS积聚可诱导NF-κB p65/RELA核转位和Ser536磷酸化。重要的是，用IκB超抑制子阻断典型的NF-κB亚单位的活性，或通过IKKα下调抑制典型的NF-κB信号，通过上调P53-p21Cip1/WAF1轴来加速HdF的早衰；但抑制典型的NF-βB通路加剧了H_2O_2诱导的A549细胞的凋亡。高密度脂蛋白的过早老化伴随着γ-H_2AX染色质沉积、衰老相关的异染色斑和β-半乳糖苷酶染色。P53基因下调消除了载体对照和IκBαSR表达的hdf在功能上将规范的依赖于nf-κB的p53水平控制与ROS诱导的hdf诱导的hdf衰老联系在一起。我们得出结论，在正常和人类肿瘤细胞中，IKKβ驱动的典型的NF-κB信号对ROS反应的结果具有不同的功能作用，分别通过保护它们免受依赖于DDR的过早衰老和凋亡。
DNA damage responses (DDR) invoke senescence or apoptosis depending on stimulus intensity and the degree of activation of the p53-p21Cip1/Waf1 axis; but the functional impact of NF-κB signaling on these different outcomes in normal vs. human cancer cells remains poorly understood. We investigated the NF-κB-dependent effects and mechanism underlying reactive oxygen species (ROS)-mediated DDR outcomes of normal human lung fibroblasts (HDFs) and A549 human lung cancer epithelial cells. To activate DDR, ROS accumulation was induced by different doses of H2O2. The effect of ROS induction caused the G2-M phase cell cycle arrest of both human cell types. However, ROS-mediated DDR eventually culminated in different end points with HDFs undergoing premature senescence and A549 cancer cells succumbing to apoptosis. NF-κB p65/RelA nuclear translocation and Ser536 phosphorylation were induced in response to H2O2-mediated ROS accumulation. Importantly, blocking the activities of canonical NF-κB subunits with an IκBα super-repressor or suppressing canonical NF-κB signaling by IKKβ knock-down accelerated HDF premature senescence by up-regulating the p53-p21Cip1/Waf1 axis; but inhibiting the canonical NF-κB pathway exacerbated H2O2-induced A549 cell apoptosis. HDF premature ageing occurred in conjunction with γ-H2AX chromatin deposition, senescence-associated heterochromatic foci and beta-galactosidase staining. P53 knock-down abrogated H2O2-induced premature senescence of vector control- and IκBαSR-expressing HDFs functionally linking canonical NF-κB-dependent control of p53 levels to ROS-induced HDF senescence. We conclude that IKKβ-driven canonical NF-κB signaling has different functional roles for the outcome of ROS responses in the contexts of normal vs. human tumor cells by respectively protecting them against DDR-dependent premature senescence and apoptosis.
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