Summary
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.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Collins, L.G., Haines, C., Perkel, R., and Enck, R.E. (2007) Lung cancer: diagnosis and management. Am Fam Physician 75, 56–63.
Molina, J.R., Adjei, A.A., and Jett, J.R. (2006) Advances in chemotherapy of non-small cell lung cancer. Chest 130, 1211–9.
Kreutzer, M., Fauti, T., Kaddatz, K., Seifart, C., Neubauer, A., Schweer, H., Komhoff, M., Muller-Brusselbach, S., and Muller, R. (2007) Specific components of prostanoid-signaling pathways are present in non-small cell lung cancer cells. Oncol Rep 18, 497–501.
Krysan, K., Reckamp, K.L., Sharma, S., and Dubinett, S.M. (2006) The potential and rationale for COX-2 inhibitors in lung cancer. Anticancer Agents Med Chem 6, 209–20.
Regan, J.W. (2003) EP2 and EP4 prostanoid receptor signaling. Life Sci 74, 143–53.
Han, S., Ritzenthaler, J.D., Wingerd, B., Rivera, H.N., and Roman, J. (2007) Extracellular matrix fibronectin increases prostaglandin E2 receptor subtype EP4 in lung carcinoma cells through multiple signaling pathways: the role of AP-2. J Biol Chem 282, 7961–72.
Dohadwala, M., Batra, R.K., Luo, J., Lin, Y., Krysan, K., Pold, M., Sharma, S., and Dubinett, S.M. (2002) Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion. Biol Chem 277, 50828–33.
Peters, J.M., Lee, S.S., Li, W., Ward, J.M., Gavrilova, O., Everett, C., Reitman, M.L., Hudson, L.D., and Gonzalez, F.J. (2000) Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta). Mol Cell Biol 20, 5119–28.
Yang, L., Huang, Y., Porta, R., Yanagisawa, K., Gonzalez, A., Segi, E., Johnson, D.H., Narumiya, S., and Carbone, D.P. (2006) Host and direct antitumor effects and profound reduction in tumor metastasis with selective EP4 receptor antagonism. Cancer Res 66, 9665–72.
Cherukuri, D.P., Chen, X.B., Goulet, A.C., Young, R.N., Han, Y., Heimark, R.L., Regan, J.W., Meuillet, E., and Nelson, M.A. (2007) The EP4 receptor antagonist, L-161,982, blocks prostaglandin E2-induced signal trans-duction and cell proliferation in HCA-7 colon cancer cells. Exp Cell Res 313, 2969–79.
Acknowledgments
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.).
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer Science+Business Media, LLC
About this protocol
Cite this protocol
Ritzenthaler, J.D., Roman, J., Han, S. (2009). PPARβ/δ Agonist Increases the Expression of PGE2 Receptor Subtype EP4 in Human Lung Carcinoma Cells. In: Kozlov, S.V. (eds) Inflammation and Cancer. Methods in Molecular Biology™, vol 512. Humana Press. https://doi.org/10.1007/978-1-60327-530-9_17
Download citation
DOI: https://doi.org/10.1007/978-1-60327-530-9_17
Publisher Name: Humana Press
Print ISBN: 978-1-60327-529-3
Online ISBN: 978-1-60327-530-9
eBook Packages: Springer Protocols