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J. Biol. Chem. 278 (37): 35451-35457

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Prostaglandin E2 Regulates Cell Migration via the Intracellular Activation of the Epidermal Growth Factor Receptor*

F. Gregory Buchanan {ddagger}, Dingzhi Wang {ddagger}, Francesca Bargiacchi §, and Raymond N. DuBois {ddagger} ¶ || **

{ddagger}Department of Medicine and the Departments of Cell and Developmental Biology and Cancer Biology and the ||Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232 and §Molecular Oncology, Genentech Inc., San Francisco, California 94080

Abstract: Over the past decade cyclooxygenase-2-derived prostaglandins have been implicated in the development and progression of many types of cancer. Recently our laboratory has shown that treatment with prostaglandin E2 (PGE2) induces increased proliferation, migration, and invasiveness of colorectal carcinoma cells (Sheng, H., Shao, J., Washington, M. K., and DuBois, R. N. (2001) J. Biol. Chem. 276, 18075–18081). The stimulatory effects of PGE2 were dependent upon the activation of the phosphatidylinositol 3-kinase/Akt pathway. However, the exact signaling cascade responsible for phosphatidylinositol 3-kinase/Akt activation by PGE2 remains poorly defined. In the present study, we demonstrate that the PGE2-induced migration and invasion occurs via rapid transactivation and phosphorylation of the epidermal growth factor receptor (EGFR). Within minutes following treatment, PGE2 induces the activation of Akt. This effect was completely abolished by EGFR-specific tyrosine kinase inhibitors providing evidence for the role of the EGFR in this response. The rapid transactivation of the EGFR occurs via an intracellular Src-mediated event but not through the release of an extracellular epidermal growth factor-like ligand. EGFR transactivation was also observed in vivo by the direct comparison of normal and malignant human colorectal samples. These results suggest that in developing colonic carcinomas, the early effects of cyclooxygenase-2-derived PGE2 are in part mediated by the EGFR, and this transactivation is responsible for subsequent down-stream effects including the stimulation of cell migration and invasion.

Received for publication March 11, 2003. Revision received June 23, 2003.

* This work was supported in part by United States Public Health Services Grants DK 47297, P30CA-68485, DK 62112, and PO1CA-77839 (to R. N. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** Mina C. Wallace Professor and supported by the T. J. Martell Foundation and National Colon Cancer Research Association. To whom correspondence should be addressed: Dept. of Medicine/GI, MCN C-2104, Vanderbilt University Medical Center, 1161 21st Ave. S., Nashville, TN 37232-2279. Tel.: 615-343-4747; Fax: 615-343-6229; E-mail: raymond.dubois{at}

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J. Biol. Chem. 280, 26565-26572
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Cyclooxygenase-2-derived Prostaglandin E2 Promotes Human Cholangiocarcinoma Cell Growth and Invasion through EP1 Receptor-mediated Activation of the Epidermal Growth Factor Receptor and Akt.
C. Han and T. Wu (2005)
J. Biol. Chem. 280, 24053-24063
   Abstract »    Full Text »    PDF »
PGE2-induced hypertrophy of cardiac myocytes involves EP4 receptor-dependent activation of p42/44 MAPK and EGFR transactivation.
M. Mendez and M. C. LaPointe (2005)
Am J Physiol Heart Circ Physiol 288, H2111-H2117
   Abstract »    Full Text »    PDF »
Prostaglandin E2 promotes migration and adhesion in hepatocellular carcinoma cells.
R. Mayoral, A. Fernandez-Martinez, L. Bosca, and P. Martin-Sanz (2005)
Carcinogenesis 26, 753-761
   Abstract »    Full Text »    PDF »
15-Hydroxyprostaglandin Dehydrogenase Is Down-regulated in Colorectal Cancer.
M. G. Backlund, J. R. Mann, V. R. Holla, F. G. Buchanan, H.-H. Tai, E. S. Musiek, G. L. Milne, S. Katkuri, and R. N. DuBois (2005)
J. Biol. Chem. 280, 3217-3223
   Abstract »    Full Text »    PDF »
Antitumor Activity of ZD6474, a Vascular Endothelial Growth Factor-2 and Epidermal Growth Factor Receptor Small Molecule Tyrosine Kinase Inhibitor, in Combination with SC-236, a Cyclooxygenase-2 Inhibitor.
C. Tuccillo, M. Romano, T. Troiani, E. Martinelli, F. Morgillo, F. De Vita, R. Bianco, G. Fontanini, R. A. Bianco, G. Tortora, et al. (2005)
Clin. Cancer Res. 11, 1268-1276
   Abstract »    Full Text »    PDF »
Activation of the Epidermal Growth Factor Receptor by Respiratory Syncytial Virus Results in Increased Inflammation and Delayed Apoptosis.
M. M. Monick, K. Cameron, J. Staber, L. S. Powers, T. O. Yarovinsky, J. G. Koland, and G. W. Hunninghake (2005)
J. Biol. Chem. 280, 2147-2158
   Abstract »    Full Text »    PDF »
Cyclooxygenase-2 and Epidermal Growth Factor Receptor: Pharmacologic Targets for Chemoprevention.
A. J. Dannenberg, S. M. Lippman, J. R. Mann, K. Subbaramaiah, and R. N. DuBois (2005)
J. Clin. Oncol. 23, 254-266
   Abstract »    Full Text »    PDF »
Prostaglandin E2 Regulates the Complement Inhibitor CD55/Decay-accelerating Factor in Colorectal Cancer.
V. R. Holla, D. Wang, J. R. Brown, J. R. Mann, S. Katkuri, and R. N. DuBois (2005)
J. Biol. Chem. 280, 476-483
   Abstract »    Full Text »    PDF »
Identification of Nonsteroidal Anti-inflammatory Drug-activated Gene (NAG-1) as a Novel Downstream Target of Phosphatidylinositol 3-Kinase/AKT/GSK-3{beta} Pathway.
K. Yamaguchi, S.-H. Lee, T. E. Eling, and S. J. Baek (2004)
J. Biol. Chem. 279, 49617-49623
   Abstract »    Full Text »    PDF »
Endothelin-1-induced Prostaglandin E2-EP2, EP4 Signaling Regulates Vascular Endothelial Growth Factor Production and Ovarian Carcinoma Cell Invasion.
F. Spinella, L. Rosano, V. Di Castro, P. G. Natali, and A. Bagnato (2004)
J. Biol. Chem. 279, 46700-46705
   Abstract »    Full Text »    PDF »
Novel Management of Oral Cancer: A Paradigm of Predictive Oncology.
J. Sudbo (2004)
Clin. Med. Res. 2, 233-242
   Abstract »    Full Text »    PDF »
Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice.
A. E. Moran, D. H. Hunt, S. H. Javid, M. Redston, A. M. Carothers, and M. M. Bertagnolli (2004)
J. Biol. Chem. 279, 43261-43272
   Abstract »    Full Text »    PDF »
Opioids As Modulators of Cell Death and Survival--Unraveling Mechanisms and Revealing New Indications.
I. Tegeder and G. Geisslinger (2004)
Pharmacol. Rev. 56, 351-369
   Abstract »    Full Text »    PDF »
Prostaglandin EP receptors: Targets for treatment and prevention of colorectal cancer?.
M. A. Hull, S. C.W. Ko, and G. Hawcroft (2004)
Mol. Cancer Ther. 3, 1031-1039
   Abstract »    Full Text »    PDF »
Prostaglandin E2 Synergistically Enhances Receptor Tyrosine Kinase-dependent Signaling System in Colon Cancer Cells.
J. Shao, B. M. Evers, and H. Sheng (2004)
J. Biol. Chem. 279, 14287-14293
   Abstract »    Full Text »    PDF »
Cyclooxygenase 2-derived prostaglandin E2 regulates the angiogenic switch.
D. Wang and R. N. DuBois (2004)
PNAS 101, 415-416
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