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MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells.
Beke, Lijs; Kig, Cenk; Linders, Joannes T M; Boens, Shannah; Boeckx, An; van Heerde, Erika; Parade, Marc; De Bondt, An; Van den Wyngaert, Ilse; Bashir, Tarig; Ogata, Souichi; Meerpoel, Lieven; Van Eynde, Aleyde; Johnson, Christopher N; Beullens, Monique; Brehmer, Dirk; Bollen, Mathieu.
Afiliación
  • Beke L; Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Kig C; Laboratory of Biosignaling & Therapeutics, KULeuven Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, O&N1/ Box 901, Herestraat 49, 3000 Leuven, Belgium.
  • Linders JT; Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Boens S; Laboratory of Biosignaling & Therapeutics, KULeuven Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, O&N1/ Box 901, Herestraat 49, 3000 Leuven, Belgium.
  • Boeckx A; Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • van Heerde E; Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Parade M; Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • De Bondt A; Computational Sciences, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Van den Wyngaert I; Computational Sciences, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Bashir T; Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Ogata S; Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Meerpoel L; Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium.
  • Van Eynde A; Laboratory of Biosignaling & Therapeutics, KULeuven Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, O&N1/ Box 901, Herestraat 49, 3000 Leuven, Belgium.
  • Johnson CN; Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
  • Beullens M; Laboratory of Biosignaling & Therapeutics, KULeuven Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, O&N1/ Box 901, Herestraat 49, 3000 Leuven, Belgium Monique.Beullems@med.kuleuven.be Mathieu.Bollen@med.kuleuven.be dbrehmer@its.jnj.com.
  • Brehmer D; Oncology Discovery, Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium Monique.Beullems@med.kuleuven.be Mathieu.Bollen@med.kuleuven.be dbrehmer@its.jnj.com.
  • Bollen M; Laboratory of Biosignaling & Therapeutics, KULeuven Department of Cellular and Molecular Medicine, University of Leuven, Campus Gasthuisberg, O&N1/ Box 901, Herestraat 49, 3000 Leuven, Belgium Monique.Beullems@med.kuleuven.be Mathieu.Bollen@med.kuleuven.be dbrehmer@its.jnj.com.
Biosci Rep ; 35(6)2015 Oct 02.
Article en En | MEDLINE | ID: mdl-26431963
Maternal embryonic leucine zipper kinase (MELK), a serine/threonine protein kinase, has oncogenic properties and is overexpressed in many cancer cells. The oncogenic function of MELK is attributed to its capacity to disable critical cell-cycle checkpoints and reduce replication stress. Most functional studies have relied on the use of siRNA/shRNA-mediated gene silencing. In the present study, we have explored the biological function of MELK using MELK-T1, a novel and selective small-molecule inhibitor. Strikingly, MELK-T1 triggered a rapid and proteasome-dependent degradation of the MELK protein. Treatment of MCF-7 (Michigan Cancer Foundation-7) breast adenocarcinoma cells with MELK-T1 induced the accumulation of stalled replication forks and double-strand breaks that culminated in a replicative senescence phenotype. This phenotype correlated with a rapid and long-lasting ataxia telangiectasia-mutated (ATM) activation and phosphorylation of checkpoint kinase 2 (CHK2). Furthermore, MELK-T1 induced a strong phosphorylation of p53 (cellular tumour antigen p53), a prolonged up-regulation of p21 (cyclin-dependent kinase inhibitor 1) and a down-regulation of FOXM1 (Forkhead Box M1) target genes. Our data indicate that MELK is a key stimulator of proliferation by its ability to increase the threshold for DNA-damage tolerance (DDT). Thus, targeting MELK by the inhibition of both its catalytic activity and its protein stability might sensitize tumours to DNA-damaging agents or radiation therapy by lowering the DNA-damage threshold.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Azepinas / Benzamidas / Daño del ADN / Neoplasias de la Mama / Proteínas Serina-Treonina Quinasas / Inhibidores Enzimáticos Límite: Female / Humans Idioma: En Revista: Biosci Rep Año: 2015 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Azepinas / Benzamidas / Daño del ADN / Neoplasias de la Mama / Proteínas Serina-Treonina Quinasas / Inhibidores Enzimáticos Límite: Female / Humans Idioma: En Revista: Biosci Rep Año: 2015 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido