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

Autor: Murray J; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Valli E; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia; School of Women's and Children's Health, UNSW Australia, NSW 2052, Australia., Yu DMT; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia; School of Women's and Children's Health, UNSW Australia, NSW 2052, Australia., Truong AM; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia; School of Medical Sciences, UNSW Australia, NSW 2052, Australia., Gifford AJ; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia; School of Women's and Children's Health, UNSW Australia, NSW 2052, Australia; Department of Anatomical Pathology (SEALS), Prince of Wales Hospital, Randwick, NSW 2031, Australia., Eden GL; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Gamble LD; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Hanssen KM; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia; School of Medical Sciences, UNSW Australia, NSW 2052, Australia., Flemming CL; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Tan A; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Tivnan A; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Allan S; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Saletta F; Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia., Cheung L; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Ruhle M; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Schuetz JD; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA., Henderson MJ; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia; School of Women's and Children's Health, UNSW Australia, NSW 2052, Australia., Byrne JA; Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia; University of Sydney Discipline of Child and Adolescent Health, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia., Norris MD; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia; University of New South Wales Centre for Childhood Cancer Research, UNSW Australia, NSW 2052, Australia., Haber M; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia., Fletcher JI; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Australia, NSW 2052, Australia; School of Women's and Children's Health, UNSW Australia, NSW 2052, Australia. Electronic address: JFletcher@ccia.unsw.edu.au.
Jazyk: angličtina
Zdroj: European journal of cancer (Oxford, England : 1990) [Eur J Cancer] 2017 Sep; Vol. 83, pp. 132-141. Date of Electronic Publication: 2017 Jul 20.
DOI: 10.1016/j.ejca.2017.06.024
Abstrakt: 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.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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