標題: 7-Chloro-6-piperidin-1-yl-quinoline-5,8-dione (PT-262), a novel ROCK inhibitor blocks cytoskeleton function and cell migration
作者: Tsai, Chih-Chien
Liu, Huei-Fang
Hsu, Kai-Cheng
Yang, Jinn-Moon
Chen, Chinpiao
Liu, Kuang-Kai
Hsu, Tzu-Sheng
Chao, Jui-I.
生物科技學系
生物資訊及系統生物研究所
分子醫學與生物工程研究所
Department of Biological Science and Technology
Institude of Bioinformatics and Systems Biology
Institute of Molecular Medicine and Bioengineering
關鍵字: PT-262;ROCK;Cell migration;Cytoskeleton;Lung cancer
公開日期: 1-四月-2011
摘要: The 5,8-quinolinediones are precursors for producing multiple types of bioactive products. In this study, we investigated a new compound derived from 5,8-quinolinediones, 7-chloro-6-piperidin-1-yl-quinoline-5,8-dione (designated as PT-262), which markedly induced cytoskeleton remodeling and migration inhibition in lung carcinoma cells. Comparison with various cytoskeleton inhibitors, including paclitaxel, colchicine and phallacidin, the cell morphology following treatment with PT-262 was similar to phallacidin on the cell elongation and abnormal actin polymerization. However, PT-262 did not directly bind to actin filaments. ROCK (Rho-associated coiled-coil forming protein kinase) is a downstream effector of RhoA to mediate the phosphorylation of myosin light chain (MLC) and cytoskeleton reorganization. The RhoA-ROCK-MLC pathway has been shown to promote cancer cell migration and metastasis. Interestingly. PT-262 was more effective on inhibiting ROCK kinase activities than specific ROCK inhibitors Y-27632 and H-1152. PT-262 induced cytoskeleton remodeling and migration inhibition in A549 lung carcinoma cells. The total MLC and phosphorylated MLC proteins and stress fibers were blocked after treatment with PT-262. Nonetheless, the RhoA protein and GTPase activity were not altered by PT-262. A computational model suggests that PT-262 interacts with the ATP-binding site of ROCK protein. Together, these findings demonstrate that PT-262 is a new ROCK inhibitor. (C) 2011 Elsevier Inc. All rights reserved.
URI: http://dx.doi.org/10.1016/j.bcp.2011.01.009
http://hdl.handle.net/11536/9081
ISSN: 0006-2952
DOI: 10.1016/j.bcp.2011.01.009
期刊: BIOCHEMICAL PHARMACOLOGY
Volume: 81
Issue: 7
起始頁: 856
結束頁: 865
顯示於類別:期刊論文


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