PPARβ/δ 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 E2 (PGE2), and the prostag-landin E2 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 (PPARβ/δ), 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 PPARβ/δ protein and that treatment with a selective PPARβ/δ agonist, GW501516, stimulated the expression of EP4 and induced NSCLC cell proliferation. In addition, this PPARβ/δ agonist also induced EP4 promoter activity through the binding of C/EBP to the NF-IL6 site in the EP4 promoter. Therefore, PPARβ/δ activation represents a novel molecular mechanism for regulating human cancer cell growth.
Key wordsPPARβ/δ EP4 NSCLC Transfection EMSA
We would like to thank Dr. William L. Smith (University of Michigan) for providing the mouse EP4 constructs. This work was supported by American Lung Association Grant RG-10215N (S.W.H.) and by a Merit Review Grant from the Department of Veterans Affairs (J.R.).
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