Small molecule inhibitors of aurora-a induce proteasomal degradation of N-myc in childhood neuroblastoma
Markus Brockmann, Evon Poon, Teeara Berry, Anne Carstensen, Hedwig E Deubzer, Lukas Rycak, Yann Jamin, Khin Thway, Simon P Robinson, Frederik Roels, Olaf Witt, Matthias Fischer, Louis Chesler, Martin Eilers, Markus Brockmann, Evon Poon, Teeara Berry, Anne Carstensen, Hedwig E Deubzer, Lukas Rycak, Yann Jamin, Khin Thway, Simon P Robinson, Frederik Roels, Olaf Witt, Matthias Fischer, Louis Chesler, Martin Eilers
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.
Copyright © 2013 Elsevier Inc. All rights reserved.
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Source: PubMed