Suppression of the ATP-binding cassette transporter ABCC4 impairs neuroblastoma tumour growth and sensitises to irinotecan in vivo

Jayne Murray, Emanuele Valli, Denise M.T. Yu, Alan M. Truong, Andrew J. Gifford, Georgina L. Eden, Laura D. Gamble, Kimberley M. Hanssen, Claudia L. Flemming, Alvin Tan, Amanda Tivnan, Sophie Allan, Federica Saletta, Leanna Cheung, Michelle Ruhle, John D. Schuetz, Michelle J. Henderson, Jennifer A. Byrne, Murray D. Norris, Michelle HaberJamie I. Fletcher

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

The ATP-binding cassette transporter ABCC4 (multidrug resistance protein 4, MRP4) mRNA level is a strong predictor of poor clinical outcome in neuroblastoma which may relate to its export of endogenous signalling molecules and chemotherapeutic agents. We sought to determine whether ABCC4 contributes to development, growth and drug response in neuroblastoma in vivo. In neuroblastoma patients, high ABCC4 protein levels were associated with reduced overall survival. Inducible knockdown of ABCC4 strongly inhibited the growth of human neuroblastoma cells in vitro and impaired the growth of neuroblastoma xenografts. Loss of Abcc4 in the Th-MYCN transgenic neuroblastoma mouse model did not impact tumour formation; however, Abcc4-null neuroblastomas were strongly sensitised to the ABCC4 substrate drug irinotecan. Our findings demonstrate a role for ABCC4 in neuroblastoma cell proliferation and chemoresistance and provide rationale for a strategy where inhibition of ABCC4 should both attenuate the growth of neuroblastoma and sensitise tumours to ABCC4 chemotherapeutic substrates.

Original languageEnglish
Pages (from-to)132-141
Number of pages10
JournalEuropean Journal of Cancer
Volume83
DOIs
Publication statusPublished or Issued - Sep 2017

Keywords

  • ABCC4
  • Chemotherapy
  • Drug resistance
  • Neuroblastoma
  • Xenograft

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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