English   español  
Por favor, use este identificador para citar o enlazar a este item: http://hdl.handle.net/10261/168852
COMPARTIR / IMPACTO:
Estadísticas
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:
Título

Synthetic lethality interaction between aurora kinases and CHEK1 inhibitors in ovarian cancer

AutorAlcaraz-Sanabria, Ana; Nieto-Jiménez, Cristina; Corrales-Sánchez, Verónica; Serrano-Oviedo, Leticia; Andrés-Pretel, Fernando; Montero, Juan Carlos ; Burgos, Miguel; Llopis, Juan; Galán-Moya, Eva María; Pandiella, Atanasio ; Ocaña, Alberto
Fecha de publicación2017
EditorAmerican Association for Cancer Research
CitaciónMolecular Cancer Therapeutics 16(11): 2552-2562 (2017)
ResumenOvarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and Western blot analysis. Impact on stem cell properties was evaluated by flow cytometry analysis of surface markers and sphere formation assays. Gene expression analyses followed by functional annotation identified a series of deregulated genes that belonged to cell cycle, including AURKA/B, TTK kinase, and CHEK1. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. AURKA and CHEK1 inhibitors showed a synergistic interaction in different cellular models. Combination of alisertib and LY2603618 triggered apoptosis, reduced the stem cell population, and increased the effect of taxanes and platinum compounds. Finally, expression of AURKA and CHEK1 was linked with detrimental outcome in patients. Our data describe a synthetic lethality interaction between CHEK1 and AURKA inhibitors with potential translation to the clinical setting.
Versión del editorhttps://doi.org/10.1158/1535-7163.MCT-17-0223
URIhttp://hdl.handle.net/10261/168852
Identificadoresdoi: 10.1158/1535-7163.MCT-17-0223
e-issn: 1538-8514
issn: 1535-7163
Aparece en las colecciones: (IBMCC) Artículos
Ficheros en este ítem:
Fichero Descripción Tamaño Formato  
syntcanc.pdf1,92 MBAdobe PDFVista previa
Visualizar/Abrir
Mostrar el registro completo
 

Artículos relacionados:


NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.