title: Cyclooxygenase-2 transactivates the epidermal growth factor receptor through specific E-prostanoid receptors and tumor necrosis factor-alpha converting enzyme.
abstract: 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.
authors.affiliation: Huntsman Cancer Institute, United States.
authors.forename: Mazin A
authors.initials: MA
authors.lastname: Al-Salihi
authors.forename: Scott C
authors.initials: SC
authors.lastname: Ulmer
authors.forename: Thao
authors.initials: T
authors.lastname: Doan
authors.forename: Cory D
authors.initials: CD
authors.lastname: Nelson
authors.forename: Tracy
authors.initials: T
authors.lastname: Crotty
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Prescott
authors.forename: Diana M
authors.initials: DM
authors.lastname: Stafforini
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Topham
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D019556:COS Cells; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D066246:ErbB Receptors / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D016211:Transforming Growth Factor alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D066246:ErbB Receptors; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D015232:Dinoprostone