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

Item Type:Article
Title:Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma
Creators Name:Brockmann, M. and Poon, E. and Berry, T. and Carstensen, A. and Deubzer, H.E. and Rycak, L. and Jamin, Y. and Thway, K. and Robinson, S.P. and Roels, F. and Witt, O. and Fischer, M. and Chesler, L. and Eilers, M.
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.
Keywords:Antineoplastic Agents, Aurora Kinase A, Aurora Kinases, Azepines, Benzazepines, Cell Cycle Proteins, Cyclohexanecarboxylic Acids, F-Box Proteins, F-Box-WD Repeat-Containing Protein 7, Neuroblastoma, Proteasome Endopeptidase Complex, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-myc, Pyrimidines, Thiazoles, Tumor Cell Line, Ubiquitin-Protein Ligases, Animals, Mice
Source:Cancer Cell
ISSN:1535-6108
Volume:24
Number:1
Page Range:75-89
Date:8 July 2013
Additional Information:Erratum in: Cancer Cell 30(2):357.
Official Publication:https://doi.org/10.1016/j.ccr.2013.05.005
PubMed:View item in PubMed

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