Tumor necrosis factor-alpha increases reactive oxygen species by inducing spermine oxidase in human lung epithelial cells: a potential mechanism for inflammation-induced carcinogenesis.

Abstract

Inflammation has been implicated in the development of many human epithelial cancers, including those of the stomach, lung, colon, and prostate. Tumor necrosis factor-alpha (TNF-alpha) is a potent pleiotropic, proinflammatory cytokine produced by many cells in response to injury and inflammation. Here, we show that TNF-alpha 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-alpha-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 H(2)O(2). Inhibition of TNF-alpha-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 H(2)O(2) 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.

• Authors: Naveen Babbar, Robert A Casero Jr
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 23 Pg. 11125-30 (Dec 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 17145855 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• RNA, Small Interfering
• Reactive Oxygen Species
• Tumor Necrosis Factor-alpha
• Spermine
• Hydrogen Peroxide
• Oxidoreductases Acting on CH-NH Group Donors
• Acetyltransferases
• diamine N-acetyltransferase

Topics

• Acetyltransferases (genetics, metabolism)
• Aged
• Amino Acid Sequence
• Blotting, Western
• Cell Line
• Cell Line, Transformed
• DNA Damage
• Dose-Response Relationship, Drug
• Epithelial Cells (cytology, drug effects, metabolism)
• Female
• Humans
• Hydrogen Peroxide (metabolism)
• Inflammation (complications, genetics, metabolism)
• Lung (cytology)
• Molecular Sequence Data
• Neoplasms (etiology, genetics, metabolism)
• Oxidation-Reduction (drug effects)
• Oxidoreductases Acting on CH-NH Group Donors (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Reactive Oxygen Species (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Spermine (metabolism)
• Transfection
• Tumor Necrosis Factor-alpha (pharmacology)
• Polyamine Oxidase