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Published Online November 17, 2005
Science DOI: 10.1126/science.1116221

Reports

Submitted on June 16, 2005
Accepted on November 2, 2005

Prostaglandin E2 Promotes Colon Cancer Cell Growth Through a Novel Gs-Axin-{beta}-Catenin Signaling Axis

Maria Domenica Castellone 1, Hidemi Teramoto 2, Bart O. Williams 3, Kirk M. Druey 4, J. Silvio Gutkind 1*

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 49503-2518, 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.
J. Silvio Gutkind , E-mail: sg39v{at}nih.gov

How cyclooxygenase-2 (COX-2) and its pro-inflammatory metabolite, prostaglandin E2 (PGE2), enhance colon cancer progression remains poorly understood. We show that PGE2 stimulates colon cancer cell growth through its heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor, EP2, by a signaling route that involves the activation of phosphoinositide 3-kinase and the protein kinase AKT by free G protein {beta}{gamma} subunits and the direct association of the G protein {alpha}s subunit with the RGS domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3{beta} from its complex with axin, thereby relieving the inhibitory phosphorylation of {beta}-catenin and activating its signaling pathway. These findings may provide a molecular framework for the future evaluation of chemopreventive strategies for colorectal cancer.


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