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Title: Pharmacological inhibition of microsomal prostaglandin e synthase-1 suppresses epidermal growth factor receptor-mediated tumor growth and angiogenesis.
Authors: Finetti, Federica 
Terzuoli, Erika
Bocci, Elena
Coletta, I
Polenzani, L
Mangano, G
Alisi, Ma
Cazzolla, N
Giachetti, A
Ziche, Marina
Donnini, Sandra
Issue Date: 2012
Project: None 
Journal: PLOS ONE
Background: Blockade of Prostaglandin (PG) E2 production via deletion of microsomal Prostaglandin E synthase-1 (mPGES- 1) gene reduces tumor cell proliferation in vitro and in vivo on xenograft tumors. So far the therapeutic potential of the pharmacological inhibition of mPGES-1 has not been elucidated. PGE2 promotes epithelial tumor progression via multiple signaling pathways including the epidermal growth factor receptor (EGFR) signaling pathway. Methodology/Principal Findings: Here we evaluated the antitumor activity of AF3485, a compound of a novel family of human mPGES-1 inhibitors, in vitro and in vivo, in mice bearing human A431 xenografts overexpressing EGFR. Treatment of the human cell line A431 with interleukin-1beta (IL-1b) increased mPGES-1 expression, PGE2 production and induced EGFR phosphorylation, and vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) expression. AF3485 reduced PGE2 production, both in quiescent and in cells stimulated by IL-1b. AF3485 abolished IL-1b-induced activation of the EGFR, decreasing VEGF and FGF-2 expression, and tumor-mediated endothelial tube formation. In vivo, in A431 xenograft, AF3485, administered sub-chronically, decreased tumor growth, an effect related to inhibition of EGFR signalling, and to tumor microvessel rarefaction. In fact, we observed a decrease of EGFR phosphorylation, and VEGF and FGF-2 expression in tumours explanted from treated mice. Conclusion: Our work demonstrates that the pharmacological inhibition of mPGES-1 reduces squamous carcinoma growth by suppressing PGE2 mediated-EGFR signalling and by impairing tumor associated angiogenesis. These results underscore the potential of mPGES-1 inhibitors as agents capable of controlling tumor growth.
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0040576
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