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Abstracts: Abstracts of Papers Submitted to the 39th Annual Meeting of the American Pancreatic Association, November 7-8, 2008, Chicago, Illinois

AMPA RECEPTOR ANTAGONISM INHIBITS PANCREATIC CANCER GROWTH

Michalski, C. W.1; Herner, A.1; Sauliunaite, D.1; Erkan, M.1; Oliveira, T. De1; Abiatari, I.1; Esposito, I.2; Friess, H.1; Kleeff, J.1

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doi: 10.1097/01.MPA.0000335339.43332.a9
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The role of the glutamate system and particularly of AMPA receptor signalling in pancreatic ductal adenocarcinoma (PDAC) has not yet been defined. We evaluated AMPA receptor expression and signalling in PDAC using immunohistochemistry and immunocytochemistry as well as proliferation, migration and invasion assays following treatment with the AMPA receptor agonist S-(-)-5-Fluorowillardiine (FW) and/or the non-competitive antagonist Sym2206 (SYM). Phosphorylation experiments were performed on MAP kinase signaling pathways. A subcutaneous pancreatic cancer model in athymic nude mice was used to assess the effects of AMPA antagonism in-vivo. AMPA1 and AMPA2/3 receptors were found to be expressed in PDAC tissues and in pancreatic cancer cell lines at different intensities. Cell proliferation, migration and invasion were increased following treatment with FW (AMPA agonist), whereas blockade of AMPA receptors using SYM resulted in a decrease of these parameters in a dose- and time-dependent manner. Analysis of MAP kinases showed increased ERK phosphorylation following treatment with FW which was reversed by pretreatment with SYM. In-vivo experiments in athymic nude mice showed that AMPA receptor antagonism reduced subcutaneous tumor growth. Thus, blockade of AMPA receptors with the non-competitive AMPA antagonist SYM reduced pancreatic cancer cell growth via modulation of the ERK1/2 pathway. AMPA receptors are therefore a potential therapeutic target in the treatment of PDAC.

© 2008 Lippincott Williams & Wilkins, Inc.