IGF2BP1 Controls Cell Death and Drug Resistance in Rhabdomyosarcomas by Regulating Translation of CIAP1

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2014 Apr 8

PMID 24704827

Citations 33

Authors

M D Faye

S T Beug

T E Graber

N Earl

X Xiang

B Wild

S Langlois

J Michaud

K N Cowan

R G Korneluk

M Holcik

Affiliations

Soon will be listed here.

Abstract

Rhabdomyosarcoma (RMS), a neoplasm characterised by undifferentiated myoblasts, is the most common soft tissue tumour of childhood. Although aggressive treatment of RMS could provide long-term benefit, resistance to current therapies is an ongoing problem. We report here that insulin-like growth factor 2-binding protein 1 (IGF2BP1), an oncofetal protein, is expressed in RMS patient-derived cell lines and in primary tumours where it drives translation of the cellular inhibitor of apoptosis 1 (cIAP1), a key regulator of the nuclear factor-κB signalling pathway and of caspase-8-mediated cell death. We demonstrate that reducing the levels of cIAP1 in RMS, either by IGF2BP1 knockdown or by IAP antagonists, sensitises these cells to tumour necrosis factor-α-mediated cell death. Finally, we show that targeting cIAP1 by IAP antagonists delays RMS tumour growth and improve survival in mice. Our results identify IGF2BP1 as a critical translational regulator of cIAP1-mediated apoptotic resistance in RMS and advocate for the combined use of IAP antagonists and tumour necrosis factor-α as a therapeutic approach for this type of cancer.

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