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

Date Published: December 30, 2012

Publisher: Impact Journals LLC

Author(s): Sona Hubackova, Katerina Krejcikova, Jiri Bartek, Zdenek Hodny.



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 TNFα. 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 TGFb 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, TGFβ/SMAD and IL1/NFκB signaling pathways. Whereas inhibition of IL6/STAT signaling had no effect on DDR induction in bystander cells, inhibition of either TGFβ/SMAD or IL1/NFκB pathway resulted in decreased ROS production and reduced DDR in bystander cells. Simultaneous inhibition of both TGFβ/SMAD and IL1/NFκB pathways completely suppressed DDR indicating that IL1 and TGFβ cooperate to induce and/or maintain bystander senescence. Furthermore, the observed IL1- and TGFβ-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.

Partial Text

Cancer incidence in humans sharply increases with advancing age. The reason for this is thought to be multifactorial, including aging related accumulation of mutations in cellular tumor-suppressive and tumor-promoting (oncogenic) pathways and age-related disturbance of immune surveillance. Importantly, these phenomena may be causally linked to systemic escalation of chronic inflammatory reactions known to increase with age [1, 2], as inflammation per se may lead to genotoxic effects [3] and immune system disturbance [4], thereby triggering a vicious circle of amplification of cancer permissive conditions in the organism.

The enhanced secretion of various substances including cytokines is a characteristic feature shared by various forms of cellular senescence-inducing autocrine and paracrine effects in the vicinity of senescent cells [48, 49]. On the other hand, it remains relatively poorly defined whether and how the nature of the senescent secretome and thus its (patho)physiological effects depend on the cell type and the nature of the senescence inducing stimulus. Although some cytokine species are only variably present in SAS (our unpublished data and Fig. 5E), it seems that some proinflammatory cytokines are commonly present in various forms of senescence. These shared, non-variant species are therefore candidate universal effectors of the senescence-associated secretome that can induce bystander senescence in a paracrine manner. In this study we showed that cells undergoing primary (parental) replicative, oncogene- and drug-induced senescence secrete factors competent to induce enhanced ROS production, DNA damage response and, indeed, paracrine cellular senescence in normal human fibroblasts. By manipulating the signaling pathways of IL6/STAT3, IL1β/NFκB and TGFβ/SMAD, i.e. cascades that are commonly activated in these three forms of senescence, we found that the latter two are required for, and cooperate to enhance ROS production and fuel the DNA damage response observed in bystander senescent cells.





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