CCR9-mediated signaling through β-catenin and identification of a novel CCR9 antagonist

Elevated levels of chemoldne receptor CCR9 expression in solid tumors may contribute to poor patient prognosis. In this study, we characterized a novel CCR9-mediated pathway that promotes pancreatic cancer cell invasion and drug resistance, indicating that CCR9 may play a critical role in cancer progression through activation of beta-catenin. We noted that the CCL25/CCR9 axis in pancreatic cancer cells induced the activation of beta-catenin, which enhanced cell proliferation, invasion, and drug resistance. CCR9-mediated activation of beta-catenin and the resulting downstream effects were effectively inhibited by blockade of the PI3K/AKT pathway, but not by antagonism of Wnt. Importantly, we discovered that CCR9/CCL25 increased the lethal dose of gemcitabine, suggesting decreased efficacy of anti-cancer drugs with CCR9 signaling. Through in silico computational modeling, we identified candidate CCR9 antagonists and tested their effects on CCR9/beta-catenin regulation of cell signaling and drug sensitivity. When combined with gemcitabine, it resulted in synergistic cytotoxicity. Our results show that CCR9/beta-catenin signaling enhances pancreatic cancer invasiveness and chemoresistance, and may be a highly novel therapeutic target. (C) 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.