Publication Date:
2005-11-19
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Castellone, Maria Domenica -- Teramoto, Hidemi -- Williams, Bart O -- Druey, Kirk M -- Gutkind, J Silvio -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2005 Dec 2;310(5753):1504-10. Epub 2005 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4340, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16293724" target="_blank"〉PubMed〈/a〉
Keywords:
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
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
