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Prostaglandin E2 Promotes Colon Cancer Cell Growth Through a Gs-Axin-ß-Catenin Signaling Axis
Maria Domenica Castellone,1Hidemi Teramoto,2Bart O. Williams,3Kirk M. Druey,4J. Silvio Gutkind1*
How cyclooxygenase-2 (COX-2) and its proinflammatory metaboliteprostaglandin E2 (PGE2) enhance colon cancer progression remainspoorly understood. We show that PGE2 stimulates colon cancercell growth through its heterotrimeric guanine nucleotide-bindingprotein (G protein)–coupled receptor, EP2, by a signalingroute that involves the activation of phosphoinositide 3-kinaseand the protein kinase Akt by free G protein ß subunitsand the direct association of the G protein s subunit with theregulator of G protein signaling (RGS) domain of axin. Thisleads to the inactivation and release of glycogen synthase kinase3ß from its complex with axin, thereby relieving theinhibitory phosphorylation of ß-catenin and activatingits signaling pathway. These findings may provide a molecularframework for the future evaluation of chemopreventive strategiesfor colorectal cancer.
1 Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892–4340, USA. 2 Kojin Hospital, 1-710 Shikenya, Moriyama, Nagoya 463-8530, Japan. 3 Laboratory of Cell Signaling and Carcinogenesis, Van Andel Research Institute, Grand Rapids, MI 49503, USA. 4 Molecular Signal Transduction Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
* To whom correspondence should be addressed. E-mail: sg39v{at}nih.gov
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subunits and the direct association of the G protein 
s subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3ß from its complex with axin, thereby relieving the inhibitory phosphorylation of ß-catenin and activating its signaling pathway. These findings may provide a molecular framework for the future evaluation of chemopreventive strategies for colorectal cancer. 
