Tumor Necrosis Factor-α 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-A (TNF-A) is a potent pleiotropic, proinflammatory cytokine produced by many cells in response to injury and inflammation. Here, we show that TNF-A 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-A-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-A-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. (Cancer Res 2006; 66(23): 11125-30)

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

“…1A). The magnitude and time course of stimulation of SMO transcription by BFT closely parallels that seen in response to H. pylori or TNF-α (21,22). In addition to induction of SMO at the gene expression level, BFT also similarly increased SMO protein levels (Fig.…”

“…Recent reports suggest that a potential source of this inflammation-associated ROS production is the polyamine catabolic enzyme spermine oxidase (SMO), which generates H 2 O 2 as a byproduct of the back conversion of spermine to spermidine (19,20). SMO is rapidly induced by the bacterial pathogen Helicobacter pylori and the pleiotropic mediator of inflammation, tumor necrosis factor-α (TNF-α), leading to SMO-dependent ROS production and DNA damage (21,22). Elevated SMO has also been observed in tissues from human inflammatory disease patients, including H. pyloriassociated gastritis, ulcerative colitis, prostatic intraepithelial neoplasia, and prostate cancer (22)(23)(24).…”

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

“…Mice lacking TNF-α or its receptor are resistant to skin carcinogenesis (Moore et al, 1999;Arnott et al, 2004). It also initiates cancer development via inducing genetic mutation and DNA instability by enhancing intracellular ROS formation (Babbar et al, 2006). TNF also involves in tumor angiogenesis, invasive, and metastasis.…”

In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells

“…Briefly, membranes were blocked for 1 hour in Odyssey blocking buffer, per manufacturer's instructions. The primary antibodies, an affinity purified antisera to human SMO [3], SSAT [17] and a mouse anti-β-actin purchased from Santa Cruz (Santa Cruz, CA) were all used at dilutions of 1:1000 with 0.1% Tween 20 in blocking buffer for 1 h at room temperature. Following washes, blots were incubated with appropriate fluorescent dye-conjugated secondary antibodies (1:4000 each, 0.1% Tween 20, in blocking buffer protected from light, for 45 min).…”