Dual oxidase 2 and pancreatic adenocarcinoma: IFN-γ-mediated dual oxidase 2 overexpression results in H2O2-induced, ERK-associated up-regulation of HIF-1α and VEGF-A
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Yongzhong Wu1, Jennifer L. Meitzler1, Smitha Antony1, Agnes Juhasz1, Jiamo Lu1, Guojian Jiang1, Han Liu2, Melinda Hollingshead2, Diana C. Haines3, Donna Butcher3, Michaela S. Panter2, Krishnendu Roy2, James H. Doroshow1,2
1Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
2Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
3Pathology/Histotechnology Laboratory, Leidos, Inc./Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA
James H. Doroshow, email: [email protected]
Keywords: dual oxidase, NADPH oxidase, pancreatic cancer, hydrogen peroxide, angiogenesis
Received: February 19, 2016 Accepted: September 01, 2016 Published: September 15, 2016
Several NADPH oxidase family members, including dual oxidase 2 [DUOX2], are expressed in human tumors, particularly gastrointestinal cancers associated with long-standing chronic inflammation. We found previously that exposure of pancreatic ductal adenocarcinoma cells to the pro-inflammatory cytokine IFN-γ increased DUOX2 expression (but not other NADPH oxidases) leading to long-lived H2O2 production. To elucidate the pathophysiology of DUOX2-mediated H2O2 formation in the pancreas further, we demonstrate here that IFN-γ-treated BxPC-3 and CFPAC-1 pancreatic cancer cells (known to increase DUOX2 expression) produce significant levels of intracellular oxidants and extracellular H2O2 which correlate with concomitant up-regulation of VEGF-A and HIF-1α transcription. These changes are not observed in the PANC-1 line that does not increase DUOX2 expression following IFN-γ treatment. DUOX2 knockdown with short interfering RNA significantly decreased IFN-γ-induced VEGF-A or HIF-1α up-regulation, as did treatment of pancreatic cancer cells with the NADPH oxidase inhibitor diphenylene iodonium, the multifunctional reduced thiol N-acetylcysteine, and the polyethylene glycol-modified form of the hydrogen peroxide detoxifying enzyme catalase. Increased DUOX2-related VEGF-A expression appears to result from reactive oxygen-mediated activation of ERK signaling that is responsible for AP-1-related transcriptional effects on the VEGF-A promoter. To clarify the relevance of these observations in vivo, we demonstrate that many human pre-malignant pancreatic intraepithelial neoplasms and frank pancreatic cancers express substantial levels of DUOX protein compared to histologically normal pancreatic tissues, and that expression of both DUOX2 and VEGF-A mRNAs is significantly increased in surgically-resected pancreatic cancers compared to the adjacent normal pancreas.
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