Transcriptional and Non-Transcriptional Functions of PPARβ/δ in Non-Small Cell Lung Cancer.
Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a nuclear receptor involved in regulation of lipid and glucose metabolism, wound healing and inflammation. PPARβ/δ has been associated also with cancer. Here we investigated the expression of PPARβ/δ and components of the prostaglandin biosynthetic pathway in non-small cell lung cancer (NSCLC). We found increased expression of PPARβ/δ, Cox-2, cPLA(2), PGES and VEGF in human NSCLC compared to normal lung. In NSCLC cell lines PPARβ/δ activation increased proliferation and survival, while PPARβ/δ knock-down reduced viability and increased apoptosis. PPARβ/δ agonists induced Cox-2 and VEGF transcription, suggesting the existence of feed-forward loops promoting cell survival, inflammation and angiogenesis. These effects were seen only in high PPARβ/δ expressing cells, while low expressing cells were less or not affected. The effects were also abolished by PPARβ/δ knock-down or incubation with a PPARβ/δ antagonist. Induction of VEGF was due to both binding of PPARβ/δ to the VEGF promoter and PI3K activation through a non-genomic mechanism. We found that PPARβ/δ interacted with the PI3K regulatory subunit p85α leading to PI3K activation and Akt phosphorylation. Collectively, these data indicate that PPARβ/δ might be a central element in lung carcinogenesis controlling multiple pathways and representing a potential target for NSCLC treatment.
Institute of Oncology Research (IOR) and Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
Davide
D
Genini
Ramon
R
Garcia-Escudero
Giuseppina M
GM
Carbone
Carlo V
CV
Catapano
D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D007249:Inflammation; D008175:Lung Neoplasms / Q000378:metabolism*; D047494:PPAR delta / Q000096:biosynthesis* / Q000502:physiology; D048068:PPAR-beta / Q000096:biosynthesis* / Q000502:physiology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D014158:Transcription, Genetic
D004791:Enzyme Inhibitors; D047494:PPAR delta; D048068:PPAR-beta