Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis.
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.
Castellone
Maria Domenica
MD
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.
Teramoto
Hidemi
H
Williams
Bart O
BO
Druey
Kirk M
KM
Gutkind
J Silvio
JS
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*
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