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Science 310 (5753): 1504-1510

Copyright © 2005 by the American Association for the Advancement of Science

Prostaglandin E2 Promotes Colon Cancer Cell Growth Through a Gs-Axin-ß-Catenin Signaling Axis

Maria Domenica Castellone,1 Hidemi Teramoto,2 Bart O. Williams,3 Kirk M. Druey,4 J. Silvio Gutkind1*

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

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.

* To whom correspondence should be addressed. E-mail: sg39v{at}

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Cyclooxygenase-2 Derived Prostaglandin E2 Activates -Catenin in Human Cholangiocarcinoma Cells: Evidence for Inhibition of These Signaling Pathways by {omega}3 Polyunsaturated Fatty Acids.
K. Lim, C. Han, L. Xu, K. Isse, A. J. Demetris, and T. Wu (2008)
Cancer Res. 68, 553-560
   Abstract »    Full Text »    PDF »
Ligand activation of peroxisome proliferator-activated receptor-{beta}/{delta} (PPAR{beta}/{delta}) and inhibition of cyclooxygenase 2 (COX2) attenuate colon carcinogenesis through independent signaling mechanisms.
H. E. Hollingshead, M. G. Borland, A. N. Billin, T. M. Willson, F. J. Gonzalez, and J. M. Peters (2008)
Carcinogenesis 29, 169-176
   Abstract »    Full Text »    PDF »
Prostaglandin E2 Activates HPK1 Kinase Activity via a PKA-dependent Pathway.
S. Sawasdikosol, S. Pyarajan, S. Alzabin, G. Matejovic, and S. J. Burakoff (2007)
J. Biol. Chem. 282, 34693-34699
   Abstract »    Full Text »    PDF »
Loss of p53 enhances the induction of colitis-associated neoplasia by dextran sulfate sodium.
W.-C. L. Chang, R. A. Coudry, M. L. Clapper, X. Zhang, K.-L. Williams, C. S. Spittle, T. Li, and H. S. Cooper (2007)
Carcinogenesis 28, 2375-2381
   Abstract »    Full Text »    PDF »
Retinoic Acid Inhibits beta-Catenin through Suppression of Cox-2: A ROLE FOR TRUNCATED ADENOMATOUS POLYPOSIS COLI.
A. L. Eisinger, L. D. Nadauld, D. N. Shelton, S. M. Prescott, D. M. Stafforini, and D. A. Jones (2007)
J. Biol. Chem. 282, 29394-29400
   Abstract »    Full Text »    PDF »
WNTers in La Jolla.
S. Y. Sokol and K. A. Wharton Jr (2007)
Development 134, 3393-3399
   Abstract »    Full Text »    PDF »
Sequential Down-regulation of E-Cadherin with Squamous Cell Carcinoma Progression: Loss of E-Cadherin via a Prostaglandin E2-EP2 Dependent Posttranslational Mechanism.
S. Brouxhon, S. Kyrkanides, M. K. O'Banion, R. Johnson, D. A. Pearce, G. M. Centola, J.-n. H. Miller, K. H. McGrath, B. Erdle, G. Scott, et al. (2007)
Cancer Res. 67, 7654-7664
   Abstract »    Full Text »    PDF »
Molecular Scaffolds Regulate Bidirectional Crosstalk Between Wnt and Classical Seven-Transmembrane Domain Receptor Signaling Pathways.
T. Force, K. Woulfe, W. J. Koch, and R. Kerkela (2007)
Sci. STKE 2007, pe41
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Silencing of Cyclooxygenase-2 Inhibits Metastasis and Delays Tumor Onset of Poorly Differentiated Metastatic Breast Cancer Cells.
I. Stasinopoulos, D. R. O'Brien, F. Wildes, K. Glunde, and Z. M. Bhujwalla (2007)
Mol. Cancer Res. 5, 435-442
   Abstract »    Full Text »    PDF »
Nonsteroidal Anti-inflammatory Drugs Induce Colorectal Cancer Cell Apoptosis by Suppressing 14-3-3{varepsilon}.
J.-Y. Liou, D. Ghelani, S. Yeh, and K. K. Wu (2007)
Cancer Res. 67, 3185-3191
   Abstract »    Full Text »    PDF »
Prostaglandin E2 Induces the Expression of IL-1{alpha} in Colon Cancer Cells.
J. Shao and H. Sheng (2007)
J. Immunol. 178, 4097-4103
   Abstract »    Full Text »    PDF »
Gut 56, a1-a145
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Protein phosphatase 1 regulates assembly and function of the {beta}-catenin degradation complex.
W. Luo, A. Peterson, B. A. Garcia, G. Coombs, B. Kofahl, R. Heinrich, J. Shabanowitz, D. F. Hunt, H. J. Yost, and D. M. Virshup (2007)
EMBO J. 26, 1511-1521
   Abstract »    Full Text »    PDF »
The canonical Wnt signalling pathway and its APC partner in colon cancer development.
J. Schneikert and J. Behrens (2007)
Gut 56, 417-425
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Rgs1 regulates multiple G{alpha} subunits in Magnaporthe pathogenesis, asexual growth and thigmotropism.
H. Liu, A. Suresh, F. S. Willard, D. P. Siderovski, S. Lu, and N. I. Naqvi (2007)
EMBO J. 26, 690-700
   Abstract »    Full Text »    PDF »

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