Journal
ONCOGENE
Volume 34, Issue 12, Pages 1532-1541Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2014.90
Keywords
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Funding
- Canadian Institutes of Health Research [FRN 74740]
- Cancer Research Society (CRS)
- Vanier Canada Graduate Scholarship
- Frederick Banting Graduate Scholarship Doctoral Award
- Charles Best Canada Graduate Scholarship Doctoral Award
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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-kappa B 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-alpha-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-a as a therapeutic approach for this type of cancer.
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