title: Multimodal effects of small molecule ROCK and LIMK inhibitors on mitosis, and their implication as anti-leukemia agents.
abstract: Accurate chromosome segregation is vital for cell viability. Many cancer cells show chromosome instability (CIN) due to aberrant expression of the genes involved in chromosome segregation. The induction of massive chromosome segregation errors in such cancer cells by small molecule inhibitors is an emerging strategy to kill these cells selectively. Here we screened and characterized small molecule inhibitors which cause mitotic chromosome segregation errors to target cancer cell growth. We screened about 300 chemicals with known targets, and found that Rho-associated coiled-coil kinase (ROCK) inhibitors bypassed the spindle assembly checkpoint (SAC), which delays anaphase onset until proper kinetochore-microtubule interactions are established. We investigated how ROCK inhibitors affect chromosome segregation, and found that they induced microtubule-dependent centrosome fragmentation. Knockdown of ROCK1 and ROCK2 revealed their additive roles in centrosome integrity. Pharmacological inhibition of LIMK also induced centrosome fragmentation similar to that by ROCK inhibitors. Inhibition of ROCK or LIMK hyper-stabilized mitotic spindles and impaired Aurora-A activation. These results suggested that ROCK and LIMK are directly or indirectly involved in microtubule dynamics and activation of Aurora-A. Furthermore, inhibition of ROCK or LIMK suppressed T cell leukemia growth in vitro, but not peripheral blood mononuclear cells. They induced centrosome fragmentation and apoptosis in T cell leukemia cells. These results suggested that ROCK and LIMK can be a potential target for anti-cancer drugs.
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, Yahaba-cho, Shiwa-gun, Iwate, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oku
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, Yahaba-cho, Shiwa-gun, Iwate, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tareyanagi
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, Yahaba-cho, Shiwa-gun, Iwate, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takaya
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, Yahaba-cho, Shiwa-gun, Iwate, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Osaka
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, Yahaba-cho, Shiwa-gun, Iwate, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Ujiie
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, Yahaba-cho, Shiwa-gun, Iwate, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, Yahaba-cho, Shiwa-gun, Iwate, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nishiya
authors.affiliation: Department of Microbial Chemical Biology and Drug Discovery, Iwate Medical University School of Pharmaceutical Sciences, Yahaba-cho, Shiwa-gun, Iwate, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Uehara
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D018385:Centrosome / Q000187:drug effects; D043171:Chromosomal Instability; D020090:Chromosome Segregation / Q000187:drug effects; D053938:DNA Fragmentation; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D054461:Lim Kinases / Q000037:antagonists & inhibitors; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C515892:LIMK1 protein, human; D054461:Lim Kinases; D054460:rho-Associated Kinases