Peroxisome proliferator-activated receptor β/δ expression and activation in lung cancer

Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a ligand-binding inducible transcriptional factor linked to carcinogenesis. Important functions of PPARβ/δ 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/δ in tumors and adjacent normal lung tissue, and the effect of PPARβ/δ activation on lung cancer cell proliferation and apoptosis. PPARβ/δ was expressed in all studied human non-small cell lung cancers, and strong PPARβ/δ immunoreactivity was observed in epithelial cells of more than 75% of studied lung tumors. PPARβ/δ 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/δ stimulates cell proliferation (an effect that was blocked by a dominant-negative construct of PPARβ/δ), stimulates anchorage-independent cell growth, and inhibits apoptosis in lung cancer cell lines. Importantly, the activation of PPARβ/δ 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/δ exerts proliferative and anti-apoptotic effects via PI3K/Akt1 and COX-2 pathways. In conclusion, PPARβ/δ is strongly expressed in the majority of lung cancers, and its activation induces proliferative and survival response in non-small cell lung cancer.