The overall objectives of this renewal are to test the hypothesis that production of reactive oxygen species through intracellular polyamine oxidation by our recently cloned spermine oxidase (SMO) plays a significant role in inflammation-associated tumorigenesis. It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation. Although many of the inflammatory cells, cytokines, and pathways have been implicated, the molecular events linking inflammation and the necessary carcinogenic DNA mutations are unknown. Our recently discovered human SMO may provide one such link. SMO is a new member of the mammalian polyamine catabolic pathway. The products of its activity are the polyamine, spermidine, 3-aminopropanal, and the reactive oxygen species, H2O2. We have demonstrated that large, tumor-specific increases of spermine oxidase activity can lead to selective tumor cell death, thus providing a strategy for targeted antitumor therapy. However, chronic production of non-cytotoxic levels of H2O2 can have deleterious effects on normal cells, including oxidative DNA damage leading to mutations. We have recently discovered that SMO is induced in several epithelial cell types by multiple stimuli including Helicobacter pylori infection, exposure to Enterotoxigenic Bacteroides fragilis (ETBF), and exposure to the general mediators of inflammation, TNF?, IL-1? IL-6, &IL8. Both H. pylori and B. fragilis are implicated in inflammation associated cancers, gastric and colon, respectively. The production, release, and activity of TNF? and other cytokines are common responses to inflammation and injury. The fact that these stimuli all lead to increased SMO expression, H2O2 production, and measurable DNA damage that is blocked by inhibition of SMO, suggest that ROS produced by the polyamine catabolic enzyme SMO is a direct mechanism linking inflammation and potentially carcinogenic DNA damage. Thus, these data indicate that SMO may represent a new and vitally important chemopreventive target. Therefore, to assess the potential of SMO as a target for chemopreventive therapy we will: 1) define the molecular mechanisms by which inflammatory stimuli induce the expression of SMO and produce DNA damage;2) use a B. fragilis APCMinAPC?716 mouse model alone, and in combination with inhibitors of SMO and/or SMO knockout, to determine if a direct link exists between bacterial inflammation, SMO activity, ROS production and development of tumors. By understanding the pathways involved in regulating inflammation-induced SMO expression, H2O2 production, and DNA damage, and by defining their role in the initiation and progression of inflammation-associated epithelial cancers, it is likely that multiple new targets for chemopreventive therapy will emerge.

Public Health Relevance

Narrative Inflammation is associated with the development of many epithelial cancers;however, the molecular basis of this association is not clearly understood. The results presented in this application implicate hydrogen peroxide produced by spermine oxidase (SMO) in response to TNF? and other mediators of inflammation, as a direct link between inflammation and potentially carcinogenic DNA damage. A better understanding of the role of SMO in inflammation-induced cancers should aid in treatment strategies to prevent cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA098454-05A2
Application #
7580237
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Perloff, Marjorie
Project Start
2002-12-01
Project End
2013-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
5
Fiscal Year
2009
Total Cost
$330,317
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Murray-Stewart, T; Sierra, J C; Piazuelo, M B et al. (2016) Epigenetic silencing of miR-124 prevents spermine oxidase regulation: implications for Helicobacter pylori-induced gastric cancer. Oncogene 35:5480-5488
Chaturvedi, R; de Sablet, T; Asim, M et al. (2015) Increased Helicobacter pylori-associated gastric cancer risk in the Andean region of Colombia is mediated by spermine oxidase. Oncogene 34:3429-40
Johnson, Caroline H; Dejea, Christine M; Edler, David et al. (2015) Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metab 21:891-7
Chaturvedi, Rupesh; Asim, Mohammad; Barry, Daniel P et al. (2014) Spermine oxidase is a regulator of macrophage host response to Helicobacter pylori: enhancement of antimicrobial nitric oxide generation by depletion of spermine. Amino Acids 46:531-42
Zahedi, Kamyar; Barone, Sharon; Wang, Yang et al. (2014) Proximal tubule epithelial cell specific ablation of the spermidine/spermine N1-acetyltransferase gene reduces the severity of renal ischemia/reperfusion injury. PLoS One 9:e110161
Prusevich, Polina; Kalin, Jay H; Ming, Shonoi A et al. (2014) A selective phenelzine analogue inhibitor of histone demethylase LSD1. ACS Chem Biol 9:1284-93
Chaturvedi, Rupesh; Asim, Mohammad; Piazuelo, M Blanca et al. (2014) Activation of EGFR and ERBB2 by Helicobacter pylori results in survival of gastric epithelial cells with DNA damage. Gastroenterology 146:1739-51.e14
Battaglia, Valentina; DeStefano Shields, Christina; Murray-Stewart, Tracy et al. (2014) Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention. Amino Acids 46:511-9
Murray-Stewart, Tracy; Hanigan, Christin L; Woster, Patrick M et al. (2013) Histone deacetylase inhibition overcomes drug resistance through a miRNA-dependent mechanism. Mol Cancer Ther 12:2088-99
Dejea, Christine; Wick, Elizabeth; Sears, Cynthia L (2013) Bacterial oncogenesis in the colon. Future Microbiol 8:445-60

Showing the most recent 10 out of 65 publications