Prostaglandin E 2 Promotes Colon Cancer Cell Growth Through a G s -Axin-ß-Catenin Signaling Axis

Author:

Castellone Maria Domenica1234,Teramoto Hidemi1234,Williams Bart O.1234,Druey Kirk M.1234,Gutkind J. Silvio1234

Affiliation:

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.

Abstract

How cyclooxygenase-2 (COX-2) and its proinflammatory 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 βγ subunits and the direct association of the G protein α s subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3β from its complex with axin, thereby relieving the inhibitory phosphorylation of β-catenin and activating its signaling pathway. These findings may provide a molecular framework for the future evaluation of chemopreventive strategies for colorectal cancer.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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