Roles of Peroxisome Proliferator-Activated Receptor-α and -γ in the Development of Non-Small Cell Lung Cancer

Peroxisome proliferator-activated receptorPeroxisome proliferator-activated receptor (PPAR)-alpha and PPAR gamma participate in cell proliferation and apoptosis. Few studies have simultaneously investigated both PPAR alpha and PPAR gamma in lung cancers in vivo. The roles of PPAR alpha and -gamma were investigated in the development of pulmonary tumors induced in the adult A/J mouse by treatment with 4-(methylnitrosamino)-1-(3-pyridyl)-1butanone (NNK). Compared with the normal lung tissues, PPAR gamma expression was much higher in the NNK-induced lung tumor tissues. However, PPAR gamma transcriptional activity, and the levels of two major endogenous PPAR gamma ligands, 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, were significantly lower in the NNK-treated lung tissues. The ligand changes in mice were confirmed in human lung cancer tissues. Along with the alteration of PPAR gamma and its endogenous ligands, the level of PPAR alpha and its activity were increased in the NNK-induced mouse lung tumors. Treatment of mice with the synthetic PPAR gamma ligand, pioglitazone, significantly inhibited the formation of mouse lung tumors induced by NNK. Our study demonstrated that the reduction of endogenous PPAR gamma ligands and increased PPAR alpha occurred before the formation of lung tumors, indicating that the molecular changes play a role in lung carcinogenesis. The results suggest that the enhancement of PPAR gamma activity with its ligands, and the suppression of PPAR alpha with its inhibitors, may prevent the formation of lung tumors, as well as accelerate the therapy of lung cancer. Our findings may also reveal the possibility of using the level of endogenous PPAR gamma ligands and the activities of PPAR gamma or PPAR alpha as tumor markers for lung cancer.