Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor

F. Gregory Buchanan, Dingzhi Wang, Francesca Bargiacchi, Raymond N. DuBois

Research output: Contribution to journalArticle

398 Scopus citations

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 PGE 2-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 downstream effects including the stimulation of cell migration and invasion.

Original languageEnglish (US)
Pages (from-to)35451-35457
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number37
DOIs
StatePublished - Sep 12 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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