Our laboratory has completed one of the first comprehensive evaluations of the presence of NADPH oxidase family members in human tumors. We found that NADPH oxidase 5 (NOX 5)is found in melanomas and in hematologic malingancies;dual oxidase 2 is found in various gastrointestinal malignancies. We have either over-exposed or upregulated the expression of both of these human proteins in melanoma and pancreatic tumor cell model systems to understand their functions in vitro. NOX 5 overexpression has been found to downregulate p27, alter cell cycle progression, and generate considerable amounts of extracellular hydrogen peroxide after exposure to ionomycin. Duox 2 overexpression has been found to also lead to a remarkable degree of extracellular reactive oxygen metabolism, to be inducible with interferon gamma which functions, in part, by enhancing stat 1 binding to the duox 2 promoter. Both of these genes may play an important role in producing an oxidant """"""""bystander"""""""" effect. Our overall goal is to understand the function of these oxidases in human cancer, which, to date has not been explored in detail.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011076-06
Application #
8763336
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$606,614
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Roy, Krishnendu; Wu, Yongzhong; Meitzler, Jennifer L et al. (2015) NADPH oxidases and cancer. Clin Sci (Lond) 128:863-75
Hayes, Patti; Dhillon, Sandeep; O'Neill, Kim et al. (2015) Defects in NADPH Oxidase Genes NOX1 and DUOX2 in Very Early Onset Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol 1:489-502
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Esworthy, Robert S; Kim, Byung-Wook; Chow, Joni et al. (2014) Nox1 causes ileocolitis in mice deficient in glutathione peroxidase-1 and -2. Free Radic Biol Med 68:315-25
Meitzler, Jennifer L; Antony, Smitha; Wu, Yongzhong et al. (2014) NADPH oxidases: a perspective on reactive oxygen species production in tumor biology. Antioxid Redox Signal 20:2873-89
Esworthy, R Steven; Kim, Byung-Wook; Wang, Yufeng et al. (2013) The Gdac1 locus modifies spontaneous and Salmonella-induced colitis in mice deficient in either Gpx2 or Gpx1 gene. Free Radic Biol Med 65:1273-83
Doroshow, James H; Gaur, Shikha; Markel, Susan et al. (2013) Effects of iodonium-class flavin dehydrogenase inhibitors on growth, reactive oxygen production, cell cycle progression, NADPH oxidase 1 levels, and gene expression in human colon cancer cells and xenografts. Free Radic Biol Med 57:162-75
Wu, Yonghzong; Antony, Smitha; Hewitt, Stephen M et al. (2013) Functional activity and tumor-specific expression of dual oxidase 2 in pancreatic cancer cells and human malignancies characterized with a novel monoclonal antibody. Int J Oncol 42:1229-38
Wu, Yongzhong; Lu, Jiamo; Antony, Smitha et al. (2013) Activation of TLR4 is required for the synergistic induction of dual oxidase 2 and dual oxidase A2 by IFN-γ and lipopolysaccharide in human pancreatic cancer cell lines. J Immunol 190:1859-72
Antony, Smitha; Wu, Yongzhong; Hewitt, Stephen M et al. (2013) Characterization of NADPH oxidase 5 expression in human tumors and tumor cell lines with a novel mouse monoclonal antibody. Free Radic Biol Med 65:497-508

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