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Nonsteroidal anti-inflammatory drug-activated gene-1 expression inhibits urethane-induced pulmonary tumorigenesis in transgenic mice
Cancer prevention research (Philadelphia, Pa.) (2009)
  • M Cekanova, The University of Tennessee
  • S H Lee
  • M Sukhthankar
  • R Donnell
  • T E Eling
  • S M Fischer
  • Seung J Baek, The University of Tennessee

The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) inhibits gastrointestinal tumorigenesis in NAG-1 transgenic mice (C57/BL6 background). In the present study, we investigated whether the NAG-1 protein would alter urethane-induced pulmonary lesions in NAG-1 transgenic mice on an FVB background (NAG-1(Tg+/FVB)). NAG-1(Tg+/FVB) mice had both decreased number and size of urethane-induced tumors, compared with control littermates (NAG-1(Tg+/FVB) = 16 +/- 4 per mouse versus control = 20 +/- 7 per mouse, P < 0.05). Urethane-induced pulmonary adenomas and adenocarcinomas were observed in control mice; however, only pulmonary adenomas were observed in NAG-1(Tg+/FVB) mice. Urethane-induced tumors from control littermates and NAG-1(Tg+/FVB) mice highly expressed proteins in the arachidonic acid pathway (cyclooxygenases 1/2, prostaglandin E synthase, and prostaglandin E(2) receptor) and highly activated several kinases (phospho-Raf-1 and phosphorylated extracellular signal-regulated kinase 1/2). However, only urethane-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation was decreased in NAG-1(Tg+/FVB) mice. Furthermore, significantly increased apoptosis in tumors of NAG-1(Tg+/FVB) mice compared with control mice was observed as assessed by caspase-3/7 activity. In addition, fewer inflammatory cells were observed in the lung tissue isolated from urethane-treated NAG-1(Tg+/FVB) mice compared with control mice. These results paralleled in vitro assays using human A549 pulmonary carcinoma cells. Less phosphorylated p38 MAPK was observed in cells overexpressing NAG-1 compared with control cells. Overall, our study revealed for the first time that the NAG-1 protein inhibits urethane-induced tumor formation, probably mediated by the p38 MAPK pathway, and is a possible new target for lung cancer chemoprevention

  • Apoptosis,
  • Carcinogens,
  • Growth Differentiation Factor 15,
  • Immunohistochemistry,
  • In Situ Nick-End Labeling,
  • Lung Neoplasms,
  • Reverse Transcriptase Polymerase Chain Reaction,
  • Signal Transduction,
  • Urethane,
  • p38 Mitogen-Activated Protein Kinases
Publication Date
Citation Information
M Cekanova, S H Lee, M Sukhthankar, R Donnell, et al.. "Nonsteroidal anti-inflammatory drug-activated gene-1 expression inhibits urethane-induced pulmonary tumorigenesis in transgenic mice" Cancer prevention research (Philadelphia, Pa.) Vol. 2 Iss. 5 (2009)
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