Exogenous DNA enhances DUOX2 expression and function in human pancreatic cancer cells by activating the cGAS-STING signaling pathway.

Abstract

Pro-inflammatory cytokines upregulate the expression of the H2O2-producing NADPH oxidase dual oxidase 2 (DUOX2)2 which, when elevated, adversely affects survival from pancreatic ductal adenocarcinoma (PDAC). Because the cGAS-STING pathway is known to initiate pro-inflammatory cytokine expression following uptake of exogenous DNA, we examined whether activation of cGAS-STING could play a role in the generation of reactive oxygen species by PDAC cells. Here, we found that a variety of exogenous DNA species markedly increased the production of cGAMP, the phosphorylation of TBK1 and IRF3, and the translocation of phosphorylated IRF3 into the nucleus, leading to a significant, IRF3-dependent enhancement of DUOX2 expression, and a significant flux of H2O2 in PDAC cells. However, unlike the canonical cGAS-STING pathway, DNA-related DUOX2 upregulation was not mediated by NF-κB. Although exogenous IFN-β significantly increased Stat1/2-associated DUOX2 expression, intracellular IFN-β signaling that followed cGAMP or DNA exposure did not itself increase DUOX2 levels. Finally, DUOX2 upregulation subsequent to cGAS-STING activation was accompanied by the enhanced, normoxic expression of HIF-1α and VEGF-A as well as DNA double strand cleavage, suggesting that cGAS-STING signaling may support the development of an oxidative, pro-angiogenic microenvironment that could contribute to the inflammation-related genetic instability of pancreatic cancer.

• Authors: Stephen L Wang, Yongzhong Wu, Mariam Konaté, Jiamo Lu, David Mallick, Smitha Antony, Jennifer L Meitzler, Guojian Jiang, Iris Dahan, Agnes Juhasz, Becky Diebold, Krishnendu Roy, James H Doroshow
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 205 Pg. 262-274 (08 20 2023) ISSN: 1873-4596 [Electronic] United States
• PMID: 37330147 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, N.I.H., Extramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• Dual Oxidases
• Hydrogen Peroxide
• Membrane Proteins
• Nucleotidyltransferases
• DNA
• Cytokines
• DUOX2 protein, human

Topics

• Humans
• Dual Oxidases (genetics, metabolism)
• Hydrogen Peroxide (metabolism)
• Membrane Proteins (genetics, metabolism)
• Signal Transduction
• Nucleotidyltransferases (genetics, metabolism)
• DNA (metabolism)
• Cytokines
• Pancreatic Neoplasms (metabolism)
• Tumor Microenvironment