IGF2BP1 controls cell death and drug resistance in rhabdomyosarcomas by regulating translation of cIAP1.
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.
1] Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Ottawa, Canada.
M D
MD
Faye
Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
S T
ST
Beug
Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
T E
TE
Graber
Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
N
N
Earl
1] Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada [2] Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
X
X
Xiang
1] Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada [2] Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
B
B
Wild
1] Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada [2] Department of Surgery, University of Ottawa, Ottawa, ON, Canada.
S
S
Langlois
Department of Pathology and Laboratory Medicine, University of Ottawa, The Ottawa Hospital and Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
J
J
Michaud
1] Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada [2] Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada [3] Department of Surgery, University of Ottawa, Ottawa, ON, Canada.
K N
KN
Cowan
1] Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Ottawa, Canada [3] Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
R G
RG
Korneluk
1] Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Ottawa, Canada [3] Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
M
M
Holcik
D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000378:metabolism*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
C535053:AEG 40730; D000480:Alkynes; C519161:CRD-BP protein, mouse; D004151:Dipeptides; C406144:IGF2BP1 protein, human; D051034:Inhibitor of Apoptosis Proteins; C574246:LCL161; D016601:RNA-Binding Proteins; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C494833:BIRC2 protein, human; C494834:Birc2 protein, mouse; D044767:Ubiquitin-Protein Ligases