PPARγ activation extinguishes smoking carcinogen by inhibiting NNK-mediated proliferation

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)γ can arrest the growth of lung cancer. We hypothesized that PPARγ activation inhibits NNK-mediated proliferation of lung cancer cells. PPARγ expression was increased in 94.7% human lung cancer tumor tissues, compared with their paired corresponding nontumor tissues. PPARγ 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 PPARγ. 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 PPARγ transcriptional activity in NNK-treated cells and a PPARγ dominant-negative inhibitor completely suppressed the action of troglitazone, indicating that troglitazone against NNK was PPARγ- dependent. The findings reveal a novel molecular pathway of PPARγ activation against cigarette smoking-related lung cancer.