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Peroxisome Proliferator–Activated Receptor β/ Expression and Activation in Lung Cancer

¹ Division of Allergy, Pulmonary, and Critical Care Medicine, ² Division of Pathology, Department of Medicine, and ³ Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee

Correspondence and requests for reprints should be addressed to Pierre P. Massion, M.D., Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, PRB 640, 2220 Pierce Avenue, Nashville, TN 37232-6838. E-mail: pierre.massion{at}vanderbilt.edu

Peroxisome proliferator–activated receptor β/ (PPARβ/) is a ligand-binding inducible transcriptional factor linked to carcinogenesis. Important functions of PPARβ/ were demonstrated in series of human epithelial cancers; however, its role in lung cancer remains controversial. We investigated the differential expression level and localization of PPARβ/ in tumors and adjacent normal lung tissue, and the effect of PPARβ/ activation on lung cancer cell proliferation and apoptosis. PPARβ/ was expressed in all studied human non–small cell lung cancers, and strong PPARβ/ immunoreactivity was observed in epithelial cells of more than 75% of studied lung tumors. PPARβ/ expression was consistently limited to the cancer cells in tumor tissue, while in adjacent normal lung tissue it was limited predominantly to the mononuclear cells. We found that ligand-binding activation of PPARβ/ stimulates cell proliferation (an effect that was blocked by a dominant-negative construct of PPARβ/), stimulates anchorage-independent cell growth, and inhibits apoptosis in lung cancer cell lines. Importantly, the activation of PPARβ/ induces Akt phosphorylation correlated with up-regulation of PDK1, down-regulation of PTEN, and increased expression of Bcl-xL and COX-2. These findings indicate that PPARβ/ exerts proliferative and anti-apoptotic effects via PI3K/Akt1 and COX-2 pathways. In conclusion, PPARβ/ is strongly expressed in the majority of lung cancers, and its activation induces proliferative and survival response in non–small cell lung cancer.

Key Words: non–small cell lung cancer • PPARβ/ • apoptosis • proliferation

CLINICAL RELEVANCE This study provides a link between PPARβ/ activity and the progression of lung cancer. Our findings contribute to a new and important area of research in lung cancer biology, and may have therapeutic implications.