IL1-and TGF beta-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'Bystander senescence'

0441230 - ÚMG 2015 RIV US eng J - Journal Article
Hubáčková, Soňa - Krejčíková, Kateřina - Bártek, Jiří - Hodný, Zdeněk
IL1-and TGF beta-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine 'Bystander senescence'.
Aging. Roč. 4, č. 12 (2012), 932-951. ISSN 1945-4589
R&D Projects: GA ČR GA204/08/1418; GA ČR GAP301/10/1525
Institutional support: RVO:68378050
Keywords : senescence-associated secretome * DNA damage response * cytokines * JAK/STAT3 * TGF beta * NF kappa B * IL6 * IL beta * Nox4 * autocrine and paracrine signaling * tumor
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 4.696, year: 2012

Many cancers arise at sites of infection and inflammation. Cellular senescence, a permanent state of cell cycle arrest that provides a barrier against tumorigenesis, is accompanied by elevated proinflammatory cytokines such as IL1, IL6, IL8 and TNF alpha. Here we demonstrate that media conditioned by cells undergoing any of the three main forms of senescence, i.e. replicative, oncogene-and drug-induced, contain high levels of IL1, IL6, and TGF beta capable of inducing reactive oxygen species (ROS)-mediated DNA damage response (DDR). Persistent cytokine signaling and activated DDR evoke senescence in normal bystander cells, accompanied by activation of the JAK/STAT, TGF beta/SMAD and IL1/NF kappa B signaling pathways. Whereas inhibition of IL6/STAT signaling had no effect on DDR induction in bystander cells, inhibition of either TGFa/SMAD or IL1/NF kappa B pathway resulted in decreased ROS production and reduced DDR in bystander cells. Simultaneous inhibition of both TGF beta/SMAD and IL1/NF kappa B pathways completely suppressed DDR indicating that IL1 and TGF beta cooperate to induce and/or maintain bystander senescence. Furthermore, the observed IL1- and TGF beta-induced expression of NAPDH oxidase Nox4 indicates a mechanistic link between the senescence-associated secretory phenotype (SASP) and DNA damage signaling as a feature shared by development of all major forms of paracrine bystander senescence.
Permanent Link: http://hdl.handle.net/11104/0244280