Tumor necrosis factor-alpha increases reactive oxygen species by inducing spermine oxidase in human lung epithelial cells: a potential mechanism for inflammation-induced carcinogenesis.
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.
Babbar
Naveen
N
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
Casero
Robert A
RA
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000595:Amino Acid Sequence; D015153:Blotting, Western; D002460:Cell Line; D002461:Cell Line, Transformed; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013096:Spermine / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D006861:Hydrogen Peroxide; D000587:Oxidoreductases Acting on CH-NH Group Donors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013096:Spermine; D014409:Tumor Necrosis Factor-alpha; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase