The induction of cyclooxygenase-1 by a tobacco carcinogen in U937 human macrophages is correlated to the activation of NF-kappaB.
The nicotine-derived 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), present in tobacco smoke, is most likely involved in lung carcinogenesis in smokers. We demonstrated previously that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit NNK-induced lung tumorigenesis, although the mechanism(s) is unknown. The present study demonstrates that, in U937 human macrophages, cyclooxygenase (COX)-1 and -2 are involved in the bioactivation of NNK to electrophilic mutagenic intermediates. We observed that acetylsalicylic acid and NS-398 decrease COX-dependent NNK activation in U937 cells by 66 and 37%, respectively. NSAIDs also decrease prostaglandin E(2) (PGE(2)) synthesis, which is induced in a dose-dependent manner, reaching a 7-fold increase, in NNK-treated human U937 cells. We observed that NNK induces COX-1 expression and activates the nuclear factor-kappaB (NF-kappaB), in U937 cells. N:-acetyl-L-cysteine and pyrrolidinedithiocarbamate, two inhibitors of reactive oxygen species (ROS), inhibit NNK-induced PGE2 synthesis by 41 and 44%, respectively. These data suggest that ROS, generated during pulmonary metabolism of NNK could act as signal transduction messengers and activate NF-kappaB, which will subsequently induce COX-1 activity and increase PGE(2) synthesis. These results reveal a novel aspect of tobacco carcinogenesis, and give us insight into the mechanisms of chemoprevention by NSAIDs. Accordingly, inhibition of NF-kappaB activation, leading to the inhibition of COX, offers a new approach in lung cancer prevention.
Rioux
N
N
Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City G1K 7P4, Canada.
Castonguay
A
A
D016718:Arachidonic Acid / Q000378:metabolism; D001711:Biotransformation / Q000187:drug effects; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D015232:Dinoprostone / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins; D007527:Isoenzymes / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology*; D008565:Membrane Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D009602:Nitrosamines / Q000493:pharmacokinetics / Q000633:toxicity*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020298:U937 Cells
D002273:Carcinogens; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009602:Nitrosamines; D000072000:NF-KappaB Inhibitor alpha; D016718:Arachidonic Acid; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate