激酶
体内
癌症研究
结直肠癌
蛋白激酶A
医学
MAPK/ERK通路
癌症
细胞凋亡
细胞生长
药理学
内科学
化学
生物
生物化学
生物技术
作者
Dong Joon Kim,Yan Li,Kanamata Reddy,Mee‐Hyun Lee,Myoung Ok Kim,Yong‐Yeon Cho,Sungyoung Lee,Jong‐Eun Kim,Ann M. Bode,Zigang Dong
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2012-04-21
卷期号:72 (12): 3060-3068
被引量:101
标识
DOI:10.1158/0008-5472.can-11-3851
摘要
Abstract The serine-threonine mitogen-activated protein kinase kinase family member T-LAK cell–originated protein kinase (TOPK/PBK) is heavily involved in tumor development, cancer growth, apoptosis, and inflammation. Despite the identification of TOPK as a promising novel therapeutic target, no inhibitor of TOPK has yet been reported. In this study, we screened 36 drug candidates using an in vitro kinase assay and identified the novel TOPK inhibitor HI-TOPK-032. In vitro, HI-TOPK-032 strongly suppressed TOPK kinase activity but had little effect on extracellular signal–regulated kinase 1 (ERK1), c-jun—NH2—kinase 1, or p38 kinase activities. HI-TOPK-032 also inhibited anchorage-dependent and -independent colon cancer cell growth by reducing ERK-RSK phosphorylation as well as increasing colon cancer cell apoptosis through regulation of the abundance of p53, cleaved caspase-7, and cleaved PARP. In vivo, administration of HI-TOPK-032 suppressed tumor growth in a colon cancer xenograft model. Our findings therefore show that HI-TOPK-032 is a specific inhibitor of TOPK both in vitro and in vivo that may be further developed as a potential therapeutic against colorectal cancer. Cancer Res; 72(12); 3060–8. ©2012 AACR.
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