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IGF2BP1 controls cell death and drug resistance in rhabdomyosarcomas by regulating translation of cIAP1

Oncogene volume 34, pages 1532–1541 (2015)Cite this article

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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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Acknowledgements

We thank the members of the Apoptosis Research Centre and Dr Eric LaCasse in particular for critical discussions. We are grateful to Novartis Pharmaceuticals for providing LCL161 compound and Dr P Houghton (Department of Hematology-Oncology, St Jude Children's Research Hospital, Memphis, TN, USA) for the gift of RMS cell lines. This work forms part of the PhD dissertation of MDF and was supported by an operating grant from the Canadian Institutes of Health Research (FRN 74740) and Cancer Research Society (CRS) to MH. MDF was supported by the Vanier Canada Graduate Scholarship. TEG was supported by the Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award.

Author contributions

MDF and MH designed the experiments, analysed the data and wrote the manuscript. MDF performed all the experiments except for the immunohistochemistry and in vivo mouse work. XX and BW performed the immunohistochemistry staining and JM did the scoring. SB designed and performed the in vivo mouse experiments with the help of NE. TEG did the preliminary work leading to this study and participated in the design and writing of the manuscript. SL and KNC provided all the RMS tumour samples and participated in the design of related experiments. RGK participated in the design of the experiments relating to Smac mimetics. All authors reviewed the paper.

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Author notes

  1. T E Graber

    Present address: 7Current address: Montreal Neurological Institute, Rue University, Montreal, QC, Canada H3A 2B4.,

Authors and Affiliations

  1. Apoptosis Research Centre, Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada

    M D Faye, S T Beug, T E Graber, N Earl, X Xiang, B Wild, S Langlois, K N Cowan, R G Korneluk & M Holcik

  2. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada, ON

    M D Faye, R G Korneluk & M Holcik

  3. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada

    X Xiang, B Wild & K N Cowan

  4. Department of Surgery, University of Ottawa, Ottawa, ON, Canada

    S Langlois & K N Cowan

  5. Department of Pathology and Laboratory Medicine, University of Ottawa, The Ottawa Hospital and Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    J Michaud

  6. Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada

    R G Korneluk & M Holcik

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  1. M D Faye
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Correspondence to M Holcik.

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Competing interests

RGK is a scientific founder and shareholder of Aegera Therapeutics (Pharmascience Inc., Montreal, QC, Canada) that has an SMC under clinical development. The other authors declare no conflict of interest.

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Faye, M., Beug, S., Graber, T. et al. IGF2BP1 controls cell death and drug resistance in rhabdomyosarcomas by regulating translation of cIAP1. Oncogene 34, 1532–1541 (2015). https://doi.org/10.1038/onc.2014.90

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