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- Title
The epoxyeicosatrienoic acid-stimulated phosphorylation of EGF-R involves the activation of metalloproteinases and the release of HB-EGF in cancer cells.
- Authors
Li-ming CHENG; Jian-gang JIANG; Zi-yong SUN; Chen CHEN; DACKOR, Ryan T.; ZELDIN, Darryl C.; Dao-wen WANG
- Abstract
AbstractAim:To test the hypothesis that the epoxyeicosatrienoic acid (EET)-induced transactivation of EGF-R depends on the activation of metalloproteinases and the subsequent release of HB-EGF in cancer cells.Methods:Exogenous 14,15-EET were added to four human-derived cancer cell lines Tca-8113, A549, HepG2, and MDA-MB-231, or these same cell lines were transfected with a mutant CYP epoxygenase (CYP102 F87V, an active 14,15-epoxygenase). The effects of elevated EET levels on the phosphorylation of tyrosine residues in the EGF receptor and on ERK1/2 activation were then assessed.Results:Both the addition of 14,15-EET and the transfection of cells with CYP102 F87V markedly increased the phosphorylation of the tyrosine residues of EGF-R and ERK1/2, an effect that was blocked by a selective EGF-R tyrosine kinase inhibitor (tyrphostin AG1478), a broad-spectrum metalloproteinase inhibitor (1,10-phenanthroline), and an inhibitor of HB-EGF release (CRM197) in Tca-8113 cells. In addition, AG1478, 1,10-phenanthroline, and CRM197 also inhibited the tyrosine phosphorylation of EGF-R and ERK1/2 that was induced by 14,15-EET in the A549, HepG2, and MDA-MB-231 cell lines.Conclusion:These results suggest that the EET-induced transactivation of EGF-R depends on activation of metalloproteinases and the subsequent release of HB-EGF in cancer cell lines.
- Publication
Acta Pharmacologica Sinica, 2010, Vol 31, Issue 2, p211
- ISSN
1671-4083
- Publication type
Academic Journal
- DOI
10.1038/aps.2009.184