Journal
EUROPEAN JOURNAL OF CANCER
Volume 83, Issue -, Pages 132-141Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ejca.2017.06.024
Keywords
Neuroblastoma; ABCC4; Drug resistance; Chemotherapy; Xenograft
Categories
Funding
- National Health and Medical Research Council [APP1016699, APP1029543]
- Cancer Institute New South Wales [10/TPG/1-03]
- National Institutes of Health [R01CA194206, NCI P30 CA021765-35, CA21865]
- American Lebanese Syrian Associated Charities
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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. (C) 2017 Elsevier Ltd. All rights reserved.
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