Compartir
Titre
WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells
Autor(es)
Sujet
WEE1
Cyclin A
Cyclin E
P27
MLN4924
Ewing sarcoma
Fecha de publicación
2013-03-14
Éditeur
Springer Nature
Citación
Mackintosh, C., Garcia-Dominguez, D. J., Ordóñez, J. L., Ginel-Picardo, A., Smith, P. G., Sacristán, M. P., & De Alava, E. (2013). WEE1 accumulation and deregulation of S-phase proteins mediate MLN4924 potent inhibitory effect on Ewing sarcoma cells. Oncogene, 32(11), 1441-1451. doi:10.1038/ONC.2012.153
Resumen
[EN]Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor of children and young adults in which finding effective new
targeted therapies is imperative. Here, we report an in-depth preclinical study of the investigational cullin-RING ubiquitin ligase
(CRL) inhibitor MLN4924 in ES, as we have recently demonstrated the implication of a CRL component in the ES pathogenesis. First, our results support a high sensitivity of ES cells to MLN4924 growth inhibition both in vitro (14 ES cell lines tested, median
IC50¼81 nM) and in tumor xenografts (tumor regression achieved with 60 mg/kg BID, subcutaneously, n¼9). Second, we report
a dual mechanism of action of MLN4924 in ES cells: while a wide range of MLN4924 concentrations (B30–300 nM) trigger a G2
arrest that can only be rescued by WEE1 kinase inhibition or depletion, saturating doses of the drug (4300 nM) cause a delay in
S-phase progression concomitant with unbalanced CDK2-Cyclin E and CDK2-Cyclin A relative levels (accumulation of the first and depletion of the latter). The aberrant presence of CDC6 in the nucleus at late S-phase cell cycle stage confirmed the loss of CDK2-Cyclin A-specific functions. Remarkably, other mechanisms explored (P27 accumulation and DNA damage signaling pathways) were found unable to explain MLN4924 effects, strengthening the specificity of our findings and suggesting the absence of functionality of some CRL substrates accumulated in response to MLN4924. This study renders a rationale for clinical trials and contributes molecular mechanisms for a better understanding of this promising antitumoral agent.
URI
DOI
10.1038/ONC.2012.153
Versión del editor
Aparece en las colecciones
Fichier(s) constituant ce document
Nombre:
1-D1 (3 de 7)_Mackintosh-2013-WEE1 accumulation_Oncogene.pdfEmbargado hasta: 2099-09-09
Tamaño:
4.244Mo
Formato:
Adobe PDF
Descripción:
Artículo principal