Sci. STKE, 16 September 2003
CANCER BIOLOGY PGE2 Transactivation of EGFR Contributes to Cell Migration
Prostaglandins (PGs) are labile, lipid signaling molecules produced enzymatically from the product (prostaglandin H2) of the cyclooxygenase (COX) enzymes. PG molecules have well-known roles in inflammation and blood clotting and have been implicated recently in cancer progression and metastasis. Buchanan et al. investigated the mechanism by which prostaglandin E2 (PGE2) stimulated migration of LS-174T cells, a colorectal carcinoma cell line. Using various pharmacological inhibitors, the authors showed that PGE2 stimulated epidermal growth factor receptor (EGFR) phosphorylation through a Src-dependent mechanism to stimulate the phosphorylation of the kinase Akt. EGFR ligand secretion or shedding was ruled out as the mechanism of EGFR activation by treatment of the cells with either matrix metalloproteinase (MMP) inhibitors or antibodies to neutralize the activities of various EGFR ligands; neither of which blocked production of phosphorylated Akt in response to PGE2. Only EGFR tyrosine kinase inhibitors and Src kinase inhibitors, which also blocked the cellular biochemical response to PGE2, inhibited cell migration in Boyden chambers. MMP inhibitors were also effective in blocking migration through the artificial extracellular matrix Matrigel. Examination of cyclooxygenase 2 (COX-2) and the EGFR in cancerous and adjacent normal samples of human colorectal tissues showed that COX-2 protein was more abundant in cancerous samples, and those samples with the highest COX-2 levels also had the highest levels of phosphorylated EGFR. Thus, PGE2 may contribute to tumorigenesis by stimulating EGFR, and this may explain the beneficial effects of nonsteroidal anti-inflammatory drugs in cancer patients.
F. G. Buchanan, D. Wang, F. Bargiacchi, R. N. DuBois, Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J. Biol. Chem. 278, 35451-35457 (2003). [Abstract] [Full Text]
Citation: PGE2 Transactivation of EGFR Contributes to Cell Migration. Sci. STKE 2003, tw359 (2003).
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