Submitted on November 20, 2007
Revised on June 19, 2008
Peroxisome Proliferator-Activated Receptor 
/
Expression and Activation in Lung Cancer
Tetyana V Pedchenko1, Adriana L Gonzalez2, DingZhi Wang3, Raymond N DuBois3, and Pierre P Massion1*
1 Department of Medicine, Division of Allegry, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA,
2 Department of Medicine, Division of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA,
3 Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: pierre.massion{at}vanderbilt.edu.
Peroxisome proliferator-activated receptor 
/
(PPAR/) is a ligand-binding inducible transcriptional factor linked to carcinogenesis. Important functions of PPAR/ 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 PPAR/ in tumors and adjacent normal lung tissue, and the effect of PPAR/ activation on lung cancer cell proliferation and apoptosis. PPAR/ was expressed at both mRNA and protein levels in all studied human non-small lung cancers, and strong PPAR/ immunoreactivity was observed in epithelial cells of more than 75% of studied lung tumors. PPAR/ 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 PPAR/ stimulates cell proliferation, an effect that was blocked by a dominant negative construct of PPAR/, stimulates anchorage-independent cell growth and inhibits apoptosis in lung cancer cell lines. Importantly, the activation of PPARb/d induces Akt phosphorylation correlated with upregulation of PDK1, downregulation of PTEN, and increased expression of Bcl-xL and COX-2. These findings indicate that PPAR/ exerts proliferative and anti-apoptotic effect via PI3K/Akt1 and COX-2 pathways. In conclusion, PPAR/ is strongly expressed in the majority of lung cancers, and its activation induces proliferative and survival response in non-small cell lung cancer.
