PPARbeta/delta agonist increases the expression of PGE2 receptor subtype EP4 in human lung carcinoma cells.
Lung carcinoma remains one of the most common malignant tumors in the world despite recent advancements in the development of new chemotherapeutic agents for its treatment. Therefore, novel approaches for drug target discovery play an important role in the effort to help extend its dismal 5-year survival rate (<15%). Many mechanisms contribute to oncogenic transformation in carcinoma cells in the lung and recent evidence indicates that the overproduction of prostaglandin E(2) (PGE(2)), and the prostag-landin E(2) receptor subtype, EP4, promote the growth and progression of human nonsmall cell lung carcinoma (NSCLC), the most common lung carcinoma. Peroxisome proliferator-activated receptor beta/ delta (PPARbeta/delta), one of the nuclear hormone ligand-dependent transcription factors, has recently been reported to be involved in tumorigeniCity. We have shown that NSCLC cells express PPARbeta/delta protein and that treatment with a selective PPARbeta/delta agonist, GW501516, stimulated the expression of EP4 and induced NSCLC cell proliferation. In addition, this PPARbeta/delta agonist also induced EP4 promoter activity through the binding of C/EBP to the NF-IL6 site in the EP4 promoter. Therefore, PPARbeta/delta activation represents a novel molecular mechanism for regulating human cancer cell growth.
Ritzenthaler
Jeffrey D
JD
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Roman
Jesse
J
Han
ShouWei
S
D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015232:Dinoprostone / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D047494:PPAR delta / Q000819:agonists* / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists* / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013844:Thiazoles / Q000494:pharmacology
C425931:GW 501516; D047494:PPAR delta; D048068:PPAR-beta; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013844:Thiazoles; D015232:Dinoprostone