Transcriptional and Non-Transcriptional Functions of PPAR?/? in Non-Small Cell Lung Cancer.

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Transcriptional and Non-Transcriptional Functions of PPAR?/? in Non-Small Cell Lung Cancer.

PLoS One. 2012;7(9):e46009

Authors: Genini D, Garcia-Escudero R, Carbone GM, Catapano CV

Abstract
Peroxisome proliferator-activated receptor ?/? (PPAR?/?) is a nuclear receptor involved in regulation of lipid and glucose metabolism, wound healing and inflammation. PPAR?/? has been associated also with cancer. Here we investigated the expression of PPAR?/? and components of the prostaglandin biosynthetic pathway in non-small cell lung cancer (NSCLC). We found increased expression of PPAR?/?, Cox-2, cPLA(2), PGES and VEGF in human NSCLC compared to normal lung. In NSCLC cell lines PPAR?/? activation increased proliferation and survival, while PPAR?/? knock-down reduced viability and increased apoptosis. PPAR?/? 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 PPAR?/? expressing cells, while low expressing cells were less or not affected. The effects were also abolished by PPAR?/? knock-down or incubation with a PPAR?/? antagonist. Induction of VEGF was due to both binding of PPAR?/? to the VEGF promoter and PI3K activation through a non-genomic mechanism. We found that PPAR?/? interacted with the PI3K regulatory subunit p85? leading to PI3K activation and Akt phosphorylation. Collectively, these data indicate that PPAR?/? might be a central element in lung carcinogenesis controlling multiple pathways and representing a potential target for NSCLC treatment.

PMID: 23049921 [PubMed - indexed for MEDLINE]

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