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Cancer Cell. 2013 Jul 8;24(1):75-89. doi: 10.1016/j.ccr.2013.05.005. Epub 2013 Jun 20.

Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma.

Author information

1
Comprehensive Cancer Center Mainfranken and Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
2
Division of Clinical Studies and Cancer Therapeutics, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
3
CCU Pediatric Oncology, DKFZ and Department of Pediatrics 3, University Hospital Heidelberg, Germany, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
4
Institute of Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Str. 2, 35037 Marburg, Germany.
5
Division of Radiotherapy and Imaging, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
6
Division of Pathology, The Institute of Cancer Research, The Royal Marsden NHS Trust, 15 Cotswold Rd. Belmont, Sutton, Surrey SM2 5NG, UK.
7
University Children's Hospital of Cologne, and Cologne Center for Molecular Medicine (CMMC), University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
#
Contributed equally

Abstract

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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PMID:
23792191
PMCID:
PMC4298657
DOI:
10.1016/j.ccr.2013.05.005
[Indexed for MEDLINE]
Free PMC Article
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