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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 metaboliteprostaglandin E2 (PGE2) enhance colon cancer progression remainspoorly understood. We show that PGE2 stimulates colon cancercell growth through its heterotrimeric guanine nucleotide-bindingprotein (G protein)–coupled receptor, EP2, by a signalingroute that involves the activation of phosphoinositide 3-kinaseand the protein kinase Akt by free G protein ß subunitsand the direct association of the G protein s subunit with theregulator of G protein signaling (RGS) domain of axin. Thisleads to the inactivation and release of glycogen synthase kinase3ß from its complex with axin, thereby relieving theinhibitory phosphorylation of ß-catenin and activatingits signaling pathway. These findings may provide a molecularframework for the future evaluation of chemopreventive strategiesfor 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}nih.gov
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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 »
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
|Abstract »|Full Text »|PDF »
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.
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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Hematopoietic Prostaglandin D Synthase Suppresses Intestinal Adenomas in ApcMin/+ Mice.
J. M. Park, Y. Kanaoka, N. Eguchi, K. Aritake, S. Grujic, A. M. Materi, V. S. Buslon, B. L. Tippin, A. M. Kwong, E. Salido, et al. (2007)
Cancer Res.
67, 881-889
|Abstract »|Full Text »|PDF »
Role for WNT16B in human epidermal keratinocyte proliferation and differentiation.
M.-T. Teh, D. Blaydon, L. R. Ghali, S. Edmunds, E. Pantazi, M. R. Barnes, I. M. Leigh, D. P. Kelsell, and M. P. Philpott (2007)
J. Cell Sci.
120, 330-339
|Abstract »|Full Text »|PDF »
Daxx Cooperates with the Axin/HIPK2/p53 Complex to Induce Cell Death.
Q. Li, X. Wang, X. Wu, Y. Rui, W. Liu, J. Wang, X. Wang, Y.-C. Liou, Z. Ye, and S.-C. Lin (2007)
Cancer Res.
67, 66-74
|Abstract »|Full Text »|PDF »
Cross-talk between G Protein-Coupled Receptor and Epidermal Growth Factor Receptor Signaling Pathways Contributes to Growth and Invasion of Head and Neck Squamous Cell Carcinoma.
S. M. Thomas, N. E. Bhola, Q. Zhang, S. C. Contrucci, A. L. Wentzel, M. L. Freilino, W. E. Gooding, J. M. Siegfried, D. C. Chan, and J. R. Grandis (2006)
Cancer Res.
66, 11831-11839
|Abstract »|Full Text »|PDF »
Adenomatous Polyposis Coli Control of C-terminal Binding Protein-1 Stability Regulates Expression of Intestinal Retinol Dehydrogenases.
L. D. Nadauld, R. Phelps, B. C. Moore, A. Eisinger, I. T. Sandoval, S. Chidester, P. W. Peterson, E. J. Manos, B. Sklow, R. W. Burt, et al. (2006)
J. Biol. Chem.
281, 37828-37835
|Abstract »|Full Text »|PDF »
Cyclooxygenase-2 and Colorectal Cancer Chemoprevention: The {beta}-Catenin Connection.
M. D. Castellone, H. Teramoto, and J. S. Gutkind (2006)
Cancer Res.
66, 11085-11088
|Abstract »|Full Text »|PDF »
Prostaglandin E2 Induces Fibroblast Growth Factor 9 via EP3-Dependent Protein Kinase C{delta} and Elk-1 Signaling.
P.-C. Chuang, H. S. Sun, T.-M. Chen, and S.-J. Tsai (2006)
Mol. Cell. Biol.
26, 8281-8292
|Abstract »|Full Text »|PDF »
subunits and the direct association of the G protein 
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. 
