title: Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis.
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 betagamma subunits and the direct association of the G protein alphas subunit with the regulator of G protein signaling (RGS) domain of axin. This leads to the inactivation and release of glycogen synthase kinase 3beta 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.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Castellone
authors.forename: Hidemi
authors.initials: H
authors.lastname: Teramoto
authors.forename: Bart O
authors.initials: BO
authors.lastname: Williams
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D060466:Axin Protein; D002460:Cell Line; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000473:pathology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000502:physiology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D020710:RGS Proteins / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D060466:Axin Protein; C545644:PTGER2 protein, human; D020710:RGS Proteins; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D012097:Repressor Proteins; D051176:beta Catenin; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs; D015232:Dinoprostone