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PPAR Activation Extinguishes Smoking Carcinogen by Inhibiting NNK-Mediated Proliferation

¹ Department of Surgery, and ² Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong

Correspondence and requests for reprints should be addressed to George G. Chen, Ph.D., Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong. E-mail: gchen{at}cuhk.edu.hk

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

Key Words: NNK • PPAR • troglitazone • HO-1 • p21 • NF-B

CLINICAL RELEVANCE This study has revealed a novel molecular pathway by which the activation of PPAR by its ligands functions against cigarette smoking–related lung cancer. The findings not only promote our understanding of the pathogenesis of lung cancer, but may also help to design a better treatment for this malignancy.