RT Journal Article
SR Electronic
T1 Exogenous DNA upregulates DUOX2 expression and function in human pancreatic cancer cells by activating the cGAS-STING signaling pathway
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.14.491678
DO 10.1101/2022.05.14.491678
A1 Stephen L. Wang
A1 Yongzhong Wu
A1 Mariam Konaté
A1 Jiamo Lu
A1 Smitha Antony
A1 Jennifer L. Meitzler
A1 Guojian Jiang
A1 Iris Dahan
A1 Agnes Juhasz
A1 Becky Diebold
A1 Krishnendu Roy
A1 James H. Doroshow
YR 2022
UL http://biorxiv.org/content/early/2022/05/14/2022.05.14.491678.abstract
AB Pro-inflammatory cytokines upregulate the expression of the H2O2-producing NADPH oxidase dual oxidase 2 (DUOX2) 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; and 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 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.Competing Interest StatementThe authors have declared no competing interest.DUOX2dual oxidase 2ROSreactive oxygen speciesPDACpancreatic ductal adenocarcinomaNOXNADPH oxidase(cGAS)cyclic GMP-AMP Synthase(STING)Stimulator of Interferon Genes