Dissecting the phenotypes of Plk1 inhibition in cancer cells using novel kinase inhibitory chemical CBB2001
| Autor: | Feng Yin, Jing Wang, Yanchao Wang, Jun Xu, Hui Zhang, Xiaoming Zhang, Jianxian Gong, Guimiao Lin, Rongfeng Lan, Fei Lu, Zhen Yang, Yuan-Hua Ding |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Glycine
Mice Nude Cell Cycle Proteins Biology Protein Serine-Threonine Kinases PLK1 Pathology and Forensic Medicine Inhibitory Concentration 50 Mice Aurora Kinases Cell Line Tumor Neoplasms Proto-Oncogene Proteins Nitriles Animals Humans Sulfones Cyclin B1 Molecular Biology Protein Kinase Inhibitors Aurora Kinase A Cell Proliferation Mice Inbred BALB C Kinase Cyclin-dependent kinase 2 Cyclin-dependent kinase 3 Geminin Cell Biology Phenotype Amides Cell biology Thiazoles Cell culture Cancer cell Cancer research biology.protein Benzimidazoles Female Cell Division |
| Zdroj: | Laboratory investigation; a journal of technical methods and pathology. 92(10) |
| ISSN: | 1530-0307 |
| Popis: | Polo-like kinase 1 (Plk1) is a mitotic serine/threonine kinase and its kinase activity is closely interrelated to cell cycle progression, various types of cancer development and often correlates with poor prognosis. Thus, it is of prime importance to characterize the phenotypes of Plk1 inhibition in cells for drug development and clinical application. Here, we report a novel kinase inhibitory chemical, CBB2001, which specifically inhibited Plk1 kinase activity in vitro with an IC(50) of 0.39 μM. In cervical carcinoma HeLa cells, we found that treatment of CBB2001 caused mitotic cell cycle arrest (EC(50)=0.72 μM) and induction of 'polo' cells (EC(50)=0.32 μM). Interestingly, the cell cycle arrest induced by CBB2001 was associated with accumulation of Plk1 (EC(50)=0.61 μM) and Geminin (EC(50)=0.43 μM) proteins, but distinct from the phenotypes induced by Aurora kinase inhibitors. The inhibitory effects of CBB2001 were phenocopied by RNA interferences of Plk1. We also confirmed the cell cycle inhibitory effects of CBB2001 in other cancer cells. Moreover, CBB2001 inhibited the growth of HeLa cells with an IC(50) of 0.85 μM in MTT assays, which is better than that of reported Plk1 inhibitory chemicals ON01910 (IC(50)=6.46 μM) and LFM-A13 (IC(50)=37.36 μM). CBB2001 also inhibited mouse xenograft tumor growth. Furthermore, CBB2001 inhibited mitotic exit and delayed degradation of APC/C substrates, Geminin, Cyclin B1 and Aurora A. These specific phenotypes may serve as specific features for Plk1 inhibition and for Plk1-based clinic trials. |
| Databáze: | OpenAIRE |
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