Background:The senescent microenvironment is permissive to disease progression, and the role of oxidants in this process remains uncharacterized. Results: Senescent fibroblasts promote tumor invasion through redox/calcium regulation of the cytokine IL-1␣. Conclusion: Senescence-associated oxidants and calcium drive the secretory phenotype, altering the microenvironment. Significance: Targeting senescent cells with antioxidant-based therapeutics may restrict inflammation and combat age-related disease progression.

Dysregulated inflammation has been implicated in cystic fibrosis (CF) airway pathophysiology. The expression of inflammatory genes, like interleukin 8 (IL8), involves chromatin remodeling through histone acetylation. Inflammatory gene hyperacetylation could explain inflammatory mediator dysregulation seen in CF airways. CF airways are exposed to high levels of oxidative stress, and oxidative stress increases histone acetylation and inflammatory gene transcription. Loss of cystic fibrosis transmembrane conductance regulator (CFTR) may even reduce protection against oxidative stress. Consequently, increasing oxidative stress would likely lead to an imbalance of histone acetyl-transferase (HAT) and deacetylase (HDAC) stoichiometry and contribute to the heightened inflammatory response seen in the CF airway. We hypothesize that oxidative stress in CF airways causes increased acetylation of inflammatory gene promoters, contributing to transcriptional activity of these loci. Messenger RNA levels of IL8, IL6, CXCL1, CXCL2, CXCL3, and IL1 are significantly elevated in CF epithelial cell models. Histone H4 acetylation is lower at the IL8 promoter of the non-CF cell lines than the CF models. The reducing agent N-acetyl-cysteine decreases IL8 message and promoter H4 acetylation to non-CF levels, suggesting that oxidative stress contributes to IL8 expression in these models. H 2 O 2 treatment causes increased IL-8 acetylation and mRNA in all cells, but less in the CF-model cells. Together these data suggest a model in which cells without functional CFTR are under increased oxidative stress. Our data suggest intrinsic alterations in the HAT/ HDAC balance in CFTR-deficient cells, and that oxidative stress contributes to this alteration.

Reactive Oxygen Species (ROS) have emerged as cellular signaling molecules and are implicated in metastatic disease by their ability to drive invasion and migration. Here we define the signaling adaptor protein p130Cas as a key redox-responsive molecular trigger that is engaged in highly invasive metastatic bladder tumor cell lines. Endogenous shifts in steady-state H2O2 that accompany the metastatic phenotype increase p130Cas phosphorylation, membrane recruitment and association with the scaffolding protein-Crk and subsequent Rac1 activation and actin reorganization. Both enzymatic and non-enzymatic scavenging of H2O2 abrogates p130Cas-dependent signaling and the migratory and invasive activity of the metastatic bladder tumor cells. Disruption of p130Cas attenuates both invasion and migration of the metastatic variant (253J-BV). 253J-BV cells displayed an increase in global thiol oxidation and a concomitant decrease in total phosphatase activity, common target proteins of active-site cysteine oxidation. The dependence of phosphatases on regulation of p130Cas was highlighted when depletion of PTPN12 enhanced p130cas phosphorylation and the migratory behavior of a non-invasive parental bladder tumor control (253J). These data demonstrate that the metastatic phenotype is accompanied by increases in steady-state H2O2 production that drive pro-migratory signaling and suggest that antioxidant-based therapeutics may prove useful in limiting bladder tumor invasiveness.