This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Babbar, N. Articles by Casero, R. A. Search for Related Content PubMed PubMed Citation Articles by Babbar, N. Articles by Casero, R. A., Jr.

Tumor Necrosis Factor- Increases Reactive Oxygen Species by Inducing Spermine Oxidase in Human Lung Epithelial Cells: A Potential Mechanism for Inflammation-Induced Carcinogenesis

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland

Requests for reprints: Robert A. Casero, Jr., The John Hopkins Oncology Center, Bunting/Blaustein Cancer Research Building, Room 551, Baltimore, MD 21231. Phone: 410-955-8580; Fax: 410-614-9884; E-mail: rcasero{at}jhmi.edu.

Inflammation has been implicated in the development of many human epithelial cancers, including those of the stomach, lung, colon, and prostate. Tumor necrosis factor- (TNF-) is a potent pleiotropic, proinflammatory cytokine produced by many cells in response to injury and inflammation. Here, we show that TNF- exposure results in increased production of reactive oxygen species (ROS), with a concomitant increase in the production of 8-oxo-deoxyguanosine, a marker for oxidative DNA damage, in human lung bronchial epithelial cells. The source of the ROS in TNF-–treated cells was determined by both pharmacologic and small interfering RNA (siRNA) strategies to be spermine oxidase (SMO/PAOh1). SMO/PAOh1 oxidizes spermine into spermidine, 3-aminopropanal, and H₂O₂. Inhibition of TNF-–induced SMO/PAOh1 activity with MDL 72,527 or with a targeted siRNA prevented ROS production and oxidative DNA damage. Further, similar induction in SMO/PAOh1 is observed with treatment of another inflammatory cytokine, interleukin-6. The data are consistent with a model that directly links inflammation and DNA damage through the production of H₂O₂ by SMO/PAOh1. Further, these results suggest a common mechanism by which inflammation from multiple sources can lead to the mutagenic changes necessary for the development and progression of epithelial cancers. (Cancer Res 2006; 66(23): 11125-30)

This article has been cited by other articles:

				M. J. Duffy, E. McKiernan, N. O'Donovan, and P. M. McGowan Role of ADAMs in Cancer Formation and Progression Clin. Cancer Res., February 15, 2009; 15(4): 1140 - 1144. [Abstract] [Full Text] [PDF]

				K. Levanon, C. Crum, and R. Drapkin New Insights Into the Pathogenesis of Serous Ovarian Cancer and Its Clinical Impact J. Clin. Oncol., November 10, 2008; 26(32): 5284 - 5293. [Abstract] [Full Text] [PDF]

				D. E. Nowak, B. Tian, M. Jamaluddin, I. Boldogh, L. A. Vergara, S. Choudhary, and A. R. Brasier RelA Ser276 Phosphorylation Is Required for Activation of a Subset of NF-{kappa}B-Dependent Genes by Recruiting Cyclin-Dependent Kinase 9/Cyclin T1 Complexes Mol. Cell. Biol., June 1, 2008; 28(11): 3623 - 3638. [Abstract] [Full Text] [PDF]

				A. Boueiz, M. Damarla, and P. M. Hassoun Xanthine oxidoreductase in respiratory and cardiovascular disorders Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L830 - L840. [Abstract] [Full Text] [PDF]

				G. Wei, K. DeFeo, C. S. Hayes, P. M. Woster, L. Mandik-Nayak, and S. K. Gilmour Elevated Ornithine Decarboxylase Levels Activate Ataxia Telangiectasia Mutated-DNA Damage Signaling in Normal Keratinocytes Cancer Res., April 1, 2008; 68(7): 2214 - 2222. [Abstract] [Full Text] [PDF]

				G. W. Tew, E. L. Lorimer, T. J. Berg, H. Zhi, R. Li, and C. L. Williams SmgGDS Regulates Cell Proliferation, Migration, and NF-{kappa}B Transcriptional Activity in Non-small Cell Lung Carcinoma J. Biol. Chem., January 11, 2008; 283(2): 963 - 976. [Abstract] [Full Text] [PDF]