Journal
CELLULAR SIGNALLING
Volume 19, Issue 9, Pages 1956-1963Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2007.05.003
Keywords
COX-2; EGFR; prostaglandins; E-prostanoid receptor; TACE; growth factors
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Funding
- NATIONAL CANCER INSTITUTE [R01CA095463, P01CA073992, T32CA093247] Funding Source: NIH RePORTER
- NCI NIH HHS [P01-CA73992, T32-CA93247, R01 CA095463-05, T32 CA093247, R01-CA95463, P01 CA073992, R01 CA095463, P01 CA073992-09] Funding Source: Medline
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Cyclooxygenase-2 is often highly expressed in epithelial malignancies and likely has an active role in tumor development. But how it promotes tumorigenesis is not clearly defined. Recent evidence suggests that this may involve transactivation of the epidermal growth factor receptor through E-prostanoid receptors, but reports differ about the mechanism by which this occurs. We found that E-prostanoid receptors 2-4, but not 1, transactivated the epidermal growth factor receptor. This required metalloproteinase activity, leading to release of growth factors from the cell surface. Both transforming growth factor-alpha and amphiregulin were released in response to over-expression of cyclooxygenase-2, but betacellulin and heparin-binding EGF-like growth factor were not. The metalloproteinase tumor necrosis factor-alpha converting enzyme was required for proteolytic release of transforming growth factor-alpha. We also found that addition of epidermal growth factor receptor ligands to HEK293 cells induced cyclooxygenase-2 expression, suggesting that by activating epidermal growth factor receptor signaling, cyclooxygenase-2 potentially creates a self-perpetuating cycle of cell growth. Consistent with this, inhibition of cyclooxygenase-2 reduced growth of epidermal growth factor receptor over-expressing MCF-10A breast epithelial cells in three-dimensional culture. (c) 2007 Elsevier Inc. All rights reserved.
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