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

Sangjun Lee, Eileen L. Heinrich, Lily Li, Jianming Lu, Audrey H. Choi, Rachel A. Levy, Jeffrey E. Wagner, M. L.Richard Yip, Nagarajan Vaidehi, Joseph Kim

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)1599-1611
Number of pages13
JournalMolecular Oncology
Volume9
Issue number8
DOIs
StatePublished - Oct 1 2015

Bibliographical note

Funding Information:
This study was supported by the Research Scholar Grant ( 120687-RSG-11-070-01-TBE from the American Cancer Society . Additional financial support was provided by the City of Hope Comprehensive Cancer Center ( P30 CA33572-27 ).

Publisher Copyright:
© 2015 Federation of European Biochemical Societies.

Keywords

  • CCL25
  • CCR9
  • Drug resistance
  • Pancreatic cancer
  • β-catenin

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Oncology
  • Cancer Research

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