The canonical NF-¦ÊB pathway differentially protects normal and human tumor cells from ROS-induced DNA damage

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• 作者：Alex ; ros Sfikas ; Christina Batsi ; Evangelia Tselikou ; George Vartholomatos ; Nikolaos Monokrousos ; Periklis Pappas ; Savvas Christoforidis ; Theodoros Tzavaras ; Panagiotis Kanavaros ; Vassilis G. Gorgoulis ; Kenneth B. Marcu ; Evangelos Kolettas
• 关键词：NF-¦ÊB signaling ; Hydrogen peroxide ; DNA damage response ; Senescence ; Human cells
• 刊名：Cellular Signalling
• 出版年：2012
• 出版时间：November, 2012
• 年：2012
• 卷：24
• 期：11
• 页码：2007-2023
• 全文大小：3045 K

文摘

DNA damage responses (DDR) invoke senescence or apoptosis depending on stimulus intensity and the degree of activation of the p53-p21^Cip1/Waf1 axis; but the functional impact of NF-¦ÊB signaling on these different outcomes in normal vs. human cancer cells remains poorly understood. We investigated the NF-¦ÊB-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 a G2 or 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-¦ÊB p65/RelA nuclear translocation and Ser536 phosphorylation were induced in response to H₂O₂-mediated ROS accumulation. Importantly, blocking the activities of canonical NF-¦ÊB subunits with an I¦ÊB¦Á super-repressor or suppressing canonical NF-¦ÊB signaling by IKK¦Â knock-down accelerated HDF premature senescence by up-regulating the p53-p21^Cip1/Waf1 axis; but inhibiting the canonical NF-¦ÊB pathway exacerbated H₂O₂-induced A549 cell apoptosis. HDF premature aging occurred in conjunction with ¦Ã-H2AX chromatin deposition, senescence-associated heterochromatic foci and beta-galactosidase staining. p53 knock-down abrogated H₂O₂-induced premature senescence of vector control- and I¦ÊB¦ÁSR-expressing HDFs functionally linking canonical NF-¦ÊB-dependent control of p53 levels to ROS-induced HDF senescence. We conclude that IKK¦Â-driven canonical NF-¦ÊB 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.