MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells.

Abstract

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.

• Authors: Lijs Beke, Cenk Kig, Joannes T M Linders, Shannah Boens, An Boeckx, Erika van Heerde, Marc Parade, An De Bondt, Ilse Van den Wyngaert, Tarig Bashir, Souichi Ogata, Lieven Meerpoel, Aleyde Van Eynde, Christopher N Johnson, Monique Beullens, Dirk Brehmer, Mathieu Bollen
• Journal: Bioscience reports (Biosci Rep) Vol. 35 Issue 6 (Oct 02 2015) ISSN: 1573-4935 [Electronic] England
• PMID: 26431963 (Publication Type: Journal Article)
• Copyright: © 2015 Authors.

Chemical References

• Azepines
• Benzamides
• Enzyme Inhibitors
• FOXM1 protein, human
• Forkhead Box Protein M1
• Forkhead Transcription Factors
• MELK-T1
• MELK protein, human
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases

Topics

• Apoptosis (drug effects)
• Ataxia Telangiectasia Mutated Proteins (biosynthesis)
• Azepines (administration & dosage)
• Benzamides (administration & dosage)
• Breast Neoplasms (drug therapy, genetics, pathology, radiotherapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Damage (drug effects)
• Enzyme Inhibitors (administration & dosage)
• Female
• Forkhead Box Protein M1
• Forkhead Transcription Factors (biosynthesis)
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• Protein Serine-Threonine Kinases (antagonists & inhibitors, biosynthesis, genetics)