| RRC ID |
44974
|
| 著者 |
Oku Y, Tareyanagi C, Takaya S, Osaka S, Ujiie H, Yoshida K, Nishiya N, Uehara Y.
|
| タイトル |
Multimodal effects of small molecule ROCK and LIMK inhibitors on mitosis, and their implication as anti-leukemia agents.
|
| ジャーナル |
PLoS One
|
| 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.
|
| 巻・号 |
9(3)
|
| ページ |
e92402
|
| 公開日 |
2014-1-1
|
| DOI |
10.1371/journal.pone.0092402
|
| PII |
PONE-D-13-37151
|
| PMID |
24642638
|
| PMC |
PMC3958508
|
| MeSH |
Antineoplastic Agents / pharmacology*
Apoptosis
Cell Line, Tumor
Centrosome / drug effects
Chromosomal Instability
Chromosome Segregation / drug effects
DNA Fragmentation
Drug Screening Assays, Antitumor
Humans
Leukemia / drug therapy
Lim Kinases / antagonists & inhibitors
M Phase Cell Cycle Checkpoints / drug effects*
Protein Kinase Inhibitors / pharmacology*
rho-Associated Kinases / antagonists & inhibitors
|
| IF |
2.74
|
| 引用数 |
13
|
|
WOS 分野
|
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
HeLa/Fucci2(RCB2867)
Jurkat
ATN-1(RCB1440)
TL-MOR(RCB1881) |
