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