Abstract 1318: Interleukin-1 promotes enhanced functional expression of dual oxidase 2 in human pancreatic cancer cells

Abstract

Abstract Pancreatic inflammation contributes to increased risk of pancreatic adenocarcinoma (PDAC) development through the release of pro-inflammatory cytokines and generation of reactive oxygen species (ROS). Interleukin-1 (IL-1) is a major upstream pro-inflammatory cytokine secreted by malignant or microenvironmental cells that supports pancreatic tumorigenesis, invasiveness, and tumor heterogeneity. Previously, our laboratory has established that dual oxidase 2 (DUOX2), one of seven NADPH oxidase (NOX) family members, plays a critical role in H2O2-mediated host defense and chronic inflammation in the gastrointestinal tract. DUOX2 is upregulated and expressed along with its maturation factor, DUOXA2, in several human pancreatic cancer cell lines following exposure to various pro-inflammatory cytokines, including IFN-γ, IL-4, and IL-17A. Using a panel of PDAC cells lines, we report the induction of DUOX2/DUOXA2 mRNA and protein expression by both IL-1α and IL-1ß, two major agonists of IL-1. In BxPC-3, CFPAC-1 and Hs 766T (HTB-134) cells, prolonged treatment with IL-1α or IL-1ß results in transient activation of STAT1 and NF-kB signaling followed by prolonged induction of DUOX2/DUOXA2 mRNA and protein expression. Stimulation by IL-1α or IL-1ß results in a specific increase in the expression of DUOX2/DUOXA2; increased expression of other NOX family members was not observed. Activation of canonical IL-1 signaling in our PDAC cell lines was supported by the observation of IL-1-related upregulation of IL-8 (CXCL8) mRNA, a chemokine essential for neutrophil recruitment and a potent promoter of angiogenesis, in IL-1-treated PDAC cells. Moreover, when the anti-inflammatory compound anakinra (an IL-1R antagonist) was co-administered in vitro with IL-1, cytokine-induced DUOX2/DUOXA2 and CXCL8 induction was significantly suppressed. Finally, xenografts established with BxPC-3 cells demonstrated slower growth and significant downregulation of IL-1ß and DUOX2 when the immunosuppressive corticosteroid dexamethasone was administered. Given our previous findings that DUOX2 is highly expressed in the pancreas during episodes of chronic pancreatitis or pancreatic cancer, and contributes significantly to extracellular ROS formation, these studies suggest that IL-1 may play a role in promoting inflammation and tumorigenesis in pancreatic malignancies through upregulation of DUOX2. Citation Format: David J. Mallick, Yongzhong Wu, Mariam M. Konaté, Becky A. Diebold, Smitha Antony, Jennifer L. Meitzler, Guojian Jiang, Jiamo Lu, Krishnendu Roy, James H. Doroshow. Interleukin-1 promotes enhanced functional expression of dual oxidase 2 in human pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1318.