期刊
CANCER CELL
卷 24, 期 1, 页码 75-89出版社
CELL PRESS
DOI: 10.1016/j.ccr.2013.05.005
关键词
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资金
- Federal Ministry of Education and Research
- Christopher's Smile Project [CSM001X]
- SPARKS [09RMH01]
- Neuroblastoma Society [NES003X]
- Medical Research Council (MRC) [NC3R-G1000121/94513]
- Institute of Cancer Research CR-UK
- EPSRC Cancer Imaging Centre
- MRC
- Department of Health (England) [C1060/A10334]
- NHS
- Wellcome Trust [091763Z/10/Z]
- EPSRC [EP/H046526/1] Funding Source: UKRI
- Cancer Research UK [16464] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/H046526/1] Funding Source: researchfish
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G1000121/1] Funding Source: researchfish
- Sparks Charity [09RMH01] Funding Source: researchfish
Amplification of MYCN is a driver mutation in a subset of human neuroendocrine tumors, including neuroblastoma. No small molecules that target N-Myc, the protein encoded by MYCN, are clinically available. N-Myc forms a complex with the Aurora-A kinase, which protects N-Myc from proteasomal degradation. Although stabilization of N-Myc does not require the catalytic activity of Aurora-A, we show here that two Aurora-A inhibitors, MLN8054 and MLN8237, disrupt the Aurora-A/N-Myc complex and promote degradation of N-Myc mediated by the Fbxw7 ubiquitin ligase. Disruption of the Aurora-A/N-Myc complex inhibits N-Myc-dependent transcription, correlating with tumor regression and prolonged survival in a mouse model of MYCN-driven neuroblastoma. We conclude that Aurora-A is an accessible target that makes destabilization of N-Myc a viable therapeutic strategy.
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