title: EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity.
abstract: In this report we describe the contribution of prostaglandin E(2) (PGE(2)) derived from the inducible microsomal PGE-synthase type-1 (mPGES-1) to the epidermal growth factor receptor (EGFR) oncogenic drive in tumor epithelial cells and in tumor-bearing mice. EGFR stimulation upregulated expression of mPGES-1 in HT-29, A431 and A549 cancer cells. Egr-1, a transcription factor induced by EGF, mediated this response. The Egr-1 rise provoked the overexpression of mPGES-1 messenger and protein, and enhanced PGE(2) formation. These changes were suppressed either by silencing Egr-1, or by upstream blockade of EGFR or ERK1/2 signals. Further, in a clonogenic assay on tumor cells, EGF induced a florid tumorigenic phenotype, which regressed when mPGES-1 was silenced or knocked down. EGF-induced mPGES-1 overexpression in epithelial cell reduced E-cadherin expression, whereas enhancing that of vimentin, suggesting an incipient mesenchymal phenotype. Additionally, inhibiting the EGFR in mice bearing the A431 tumor, the mPGES-1 expression and the tumor growth, exhibited a parallel decline. In conclusion, these findings provide novel evidence that a tight cooperation between the EGF/EGFR and mPGES-1 leads to a significant tumorigenic gain in epithelial cells, and provide clues for controlling the vicious association.
authors.affiliation: Section of Pharmacology, Department of Biotechnology, University of Siena, and Istituto Toscano Tumori, Siena, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Donnini
authors.forename: F
authors.initials: F
authors.lastname: Finetti
authors.forename: E
authors.initials: E
authors.lastname: Terzuoli
authors.forename: A
authors.initials: A
authors.lastname: Giachetti
authors.forename: M A
authors.initials: MA
authors.lastname: Iñiguez
authors.forename: H
authors.initials: H
authors.lastname: Hanaka
authors.forename: M
authors.initials: M
authors.lastname: Fresno
authors.forename: O
authors.initials: O
authors.lastname: Rådmark
authors.forename: M
authors.initials: M
authors.lastname: Ziche
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D051766:Early Growth Response Protein 1; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse