MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells
| Autor: | Dirk Brehmer, Christopher N. Johnson, Souichi Ogata, An Boeckx, Erika van Heerde, Lieven Meerpoel, Monique Beullens, Cenk Kig, Marc Parade, Joannes T. M. Linders, Aleyde Van Eynde, Tarig Bashir, An De Bondt, Shannah Boens, Ilse Van den Wyngaert, Mathieu Bollen, Lijs Beke |
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| Rok vydání: | 2015 |
| Předmět: |
Biophysics
Apoptosis Breast Neoplasms Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology Corrections Biochemistry Maternal embryonic leucine zipper kinase Cell Line Tumor Humans Enzyme Inhibitors Protein kinase A Molecular Biology Checkpoint Kinase 2 Cell Proliferation Cell growth Kinase Forkhead Box Protein M1 Correction Forkhead Transcription Factors Azepines Cell Biology Gene Expression Regulation Neoplastic Benzamides Cancer cell MCF-7 Cells FOXM1 Cancer research Phosphorylation Female DNA Damage |
| Zdroj: | Bioscience Reports |
| ISSN: | 1573-4935 0144-8463 |
| DOI: | 10.1042/bsr20150194 |
| Popis: | 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. ispartof: Bioscience Reports vol:35 issue:6 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
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