PPARgamma activation extinguishes smoking carcinogen by inhibiting NNK-mediated proliferation.
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.
Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
Ming-Yue
MY
Li
Michael K Y
MK
Hsin
Johnson
J
Yip
Tony S K
TS
Mok
Malcolm J
MJ
Underwood
George G
GG
Chen
D002273:Carcinogens; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002839:Chromans / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009602:Nitrosamines; D047495:PPAR gamma / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic; D000077288:Troglitazone
C493956:CDKN1A protein, human; D002273:Carcinogens; D002839:Chromans; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016328:NF-kappa B; D009602:Nitrosamines; D047495:PPAR gamma; D019253:Proto-Oncogene Proteins c-bcl-2; D045162:Thiazolidinediones; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D000077288:Troglitazone