Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis

Science. 2005 Dec 2;310(5753):1504-10. doi: 10.1126/science.1116221. Epub 2005 Nov 17.

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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Axin Protein
  • Cell Line
  • Cell Proliferation
  • Colonic Neoplasms / pathology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dinoprostone / physiology*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism*
  • Genes, Reporter
  • Humans
  • RGS Proteins / metabolism
  • Receptors, Prostaglandin E / metabolism
  • Receptors, Prostaglandin E, EP2 Subtype
  • Repressor Proteins / metabolism*
  • Signal Transduction*
  • beta Catenin / metabolism*

Substances

  • Axin Protein
  • PTGER2 protein, human
  • RGS Proteins
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP2 Subtype
  • Repressor Proteins
  • beta Catenin
  • Cyclic AMP-Dependent Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gs
  • Dinoprostone