title: NEK9 depletion induces catastrophic mitosis by impairment of mitotic checkpoint control and spindle dynamics.
abstract: NEK9 is known to play a role in spindle assembly and in the control of centrosome separation, but the consequences of NEK9 targeting in cancer cells remain to be elucidated. In this study, we used siRNA to investigate the consequences of targeting NEK9 in glioblastoma and kidney cancer cells as a first step in assessing its potential as an anti-cancer therapeutic target. Live cell imaging revealed that NEK9 depletion of U1242 glioblastoma and Caki2 kidney carcinoma cells resulted in failure of cytokinesis. Interestingly, NEK9-depleted Caki2 cells overrode mitosis under incorrect chromosome alignment and were converted to a micronucleated phenotype, leading to cell death. Whereas, the RPE1 normal epithelium cell line was refractory to abnormal mitosis upon NEK9 knockdown. Nocodazole-induced mitotic arrest was compromised after NEK9 depletion, indicating that NEK9 has an important role in mitotic checkpoint system. Taken together, we propose that NEK9 inhibition represents a novel anti-cancer strategy by induction of mitotic catastrophe via impairment of spindle dynamics, cytokinesis and mitotic checkpoint control.
authors.affiliation: Max-Planck-Institute of Biochemistry, Department of Molecular Biology, Martinsried, Germany; Shinagawa R&D Center, Daiichi Sankyo Co. Ltd., Tokyo, Japan. Electronic address: kaneta.yasuyuki.rm@daiichisanyko.co.jp.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kaneta
authors.forename: Axel
authors.initials: A
authors.lastname: Ullrich
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000628:therapy*; D048749:Cytokinesis / Q000235:genetics / Q000502:physiology; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D007680:Kidney Neoplasms / Q000628:therapy*; D059566:M Phase Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology*; D048629:Micronuclei, Chromosome-Defective; D058990:Molecular Targeted Therapy; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D034622:RNA Interference; D008941:Spindle Apparatus / Q000235:genetics / Q000502:physiology*
chemical_list: C462119:NEK9 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases
keywords: Checkpoint system; Cytokinesis; Mitotic arrest; NEK9; Therapeutic target