PPARgamma activation extinguishes smoking carcinogen by inhibiting NNK-mediated proliferation

Am J Respir Cell Mol Biol. 2010 Jan;42(1):113-22. doi: 10.1165/rcmb.2008-0463OC. Epub 2009 Apr 3.

Abstract

Among the carcinogenic chemicals of cigarette smoking, 4-(methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) is the most potent. The activation of peroxisome proliferator-activated receptor (PPAR)gamma can arrest the growth of lung cancer. We hypothesized that PPARgamma activation inhibits NNK-mediated proliferation of lung cancer cells. PPARgamma expression was increased in 94.7% human lung cancer tumor tissues, compared with their paired corresponding nontumor tissues. PPARgamma was also found to be abundant in all the lung cancer cell lines tested. Troglitazone dose-dependently inhibited the NNK-mediated proliferation of lung cancer cells that expressed PPARgamma. Troglitazone blocked NNK-induced up-regulation of HO-1, Bcl-2, and c-IAP2, and recovered Bad activity that was suppressed by NNK. NNK promoted the nuclear p21, whereas troglitazone increased cytosolic p21. Troglitazone increased PPARgamma transcriptional activity in NNK-treated cells and a PPARgamma dominant-negative inhibitor completely suppressed the action of troglitazone, indicating that troglitazone against NNK was PPARgamma-dependent. The findings reveal a novel molecular pathway of PPARgamma activation against cigarette smoking-related lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogens
  • Cell Line, Tumor
  • Cell Proliferation
  • Chromans / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Lung / metabolism
  • Lung Neoplasms / chemically induced
  • Lung Neoplasms / metabolism*
  • NF-kappa B / metabolism
  • Nitrosamines*
  • PPAR gamma / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Smoking* / adverse effects
  • Thiazolidinediones / pharmacology
  • Transcription, Genetic
  • Troglitazone

Substances

  • CDKN1A protein, human
  • Carcinogens
  • Chromans
  • Cyclin-Dependent Kinase Inhibitor p21
  • NF-kappa B
  • Nitrosamines
  • PPAR gamma
  • Proto-Oncogene Proteins c-bcl-2
  • Thiazolidinediones
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • Troglitazone