title: The canonical NF-κB pathway differentially protects normal and human tumor cells from ROS-induced DNA damage.
abstract: 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-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 H(2)O(2). 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-κB p65/RelA nuclear translocation and Ser536 phosphorylation were induced in response to H(2)O(2)-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-p21(Cip1/Waf1) axis; but inhibiting the canonical NF-κB pathway exacerbated H(2)O(2)-induced A549 cell apoptosis. HDF premature aging occurred in conjunction with γ-H2AX chromatin deposition, senescence-associated heterochromatic foci and beta-galactosidase staining. p53 knock-down abrogated H(2)O(2)-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.
authors: Cell and Molecular Physiology Unit, Laboratory of Physiology, School of Medicine, University of Ioannina, 45110 Ioannina, Greece.
authors: Alexandros
authors: A
authors: Sfikas
authors: Christina
authors: C
authors: Batsi
authors: Evangelia
authors: E
authors: Tselikou
authors: George
authors: G
authors: Vartholomatos
authors: Nikolaos
authors: N
authors: Monokrousos
authors: Periklis
authors: P
authors: Pappas
authors: Savvas
authors: S
authors: Christoforidis
authors: Theodoros
authors: T
authors: Tzavaras
authors: Panagiotis
authors: P
authors: Kanavaros
authors: Vassilis G
authors: VG
authors: Gorgoulis
authors: Kenneth B
authors: KB
authors: Marcu
authors: Evangelos
authors: E
authors: Kolettas
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D051550:I-kappa B Kinase