title: CCR9-mediated signaling through β-catenin and identification of a novel CCR9 antagonist.
abstract: Elevated levels of chemokine 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 β-catenin. We noted that the CCL25/CCR9 axis in pancreatic cancer cells induced the activation of β-catenin, which enhanced cell proliferation, invasion, and drug resistance. CCR9-mediated activation of β-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/β-catenin regulation of cell signaling and drug sensitivity. When combined with gemcitabine, it resulted in synergistic cytotoxicity. Our results show that CCR9/β-catenin signaling enhances pancreatic cancer invasiveness and chemoresistance, and may be a highly novel therapeutic target.
authors.affiliation: Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Sangjun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Eileen L
authors.initials: EL
authors.lastname: Heinrich
authors.affiliation: Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Audrey H
authors.initials: AH
authors.lastname: Choi
authors.affiliation: Department of Immunology, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Levy
authors.affiliation: Department of Immunology, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Wagner
authors.affiliation: HTS Lab, University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
authors.forename: M L Richard
authors.initials: ML
authors.lastname: Yip
authors.affiliation: Department of Immunology, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Nagarajan
authors.initials: N
authors.lastname: Vaidehi
authors.affiliation: Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California, USA. Electronic address: joekim7@yahoo.com.
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000302:isolation & purification* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019742:Chemokines, CC / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology; D054388:Receptors, CCR / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C119309:CC chemokine receptor 9; C108074:CCL25 protein, human; D019742:Chemokines, CC; D054388:Receptors, CCR; D051176:beta Catenin
keywords: CCL25; CCR9; Drug resistance; Pancreatic cancer; β-catenin