Abstract 2915: Synergistic, cytokine mediated stimulation (IL-1α/β + IL-6) of colon cancer cells reveals a novel mechanism of DNA damage facilitated by up-regulation of NOX1 and DUOX2

Abstract Inflammatory bowel diseases are states of long-term inflammation of the colon resulting from an interplay of environmental factors and dysregulated immune responses. As inflammatory exposure increases over the time frame of active disease, patients with these chronic conditions are at risk of developing colorectal cancers. Chronic inflammation is thought to contribute to cancer initiation through persistent release of reactive oxygen species (ROS), leading to genome damage. Accumulating evidence suggests inflammatory cells contribute to this process, as the secretion of cytokines and growth factors in response to gut inflammation also supports cancer cell progression. Specifically, IL-1 family members play a pivotal role in the pathogenesis of acute and chronic intestinal inflammation, regulating both innate and adaptive immune responses. To elucidate a direct link between IL-1 family cytokines, ROS generation and colorectal cancer, we observed that treatment of HT29 or T84 cells with IL-1α or IL-1β, in cooperation with IL-6, resulted in oxidant production through up-regulation of both NOX1 and DUOX2 enzymes. Up-regulation of the hydrogen peroxide generating DUOX2/DUOXA2 enzyme complex was directly associated with enhanced histone H2AX phosphorylation (γH2AX), a marker of DNA double strand breaks. Interestingly, this concentration and time-dependent induction of expression and oxidative response was absent in Caco2 cells and was not mediated by other IL-1 family members (IL-18, IL-33 or IL-37). Prior studies from our group have demonstrated significant up-regulation of DUOX2 and DUOXA2 in surgically resected colon cancer specimens compared with adjacent normal colonic epithelium. Future studies will focus on cytokine stimulation of colon organoids derived from patient tumor and adjacent non-malignant tissues to evaluate enzymatic expression and oxidant level changes in a novel patient-derived colon model system. Citation Format: Jennifer L. Meitzler, Yongzhong Wu, Agnes Juhasz, Annamaria Rapisarda, Petreena Campbell, Becky A. Diebold, Smitha Antony, Guojian Jiang, Jiamo Lu, David J. Mallick, Mariam M. Konaté, Krishnendu Roy, James H. Doroshow. Synergistic, cytokine mediated stimulation (IL-1α/β + IL-6) of colon cancer cells reveals a novel mechanism of DNA damage facilitated by up-regulation of NOX1 and DUOX2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2915.