IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine ‘Bystander senescence’

• DOI: 10.18632/aging.100520
• Publication Date: 2016-03-06T04:40:39Z
• Authors: Sona Hubackova; Katerina Krejcikova; Jiri Bartek; Zdenek Hodny
• Keywords: Senescence; NOX4; Bystander effect; Proinflammatory cytokine

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