Novel TOPK Inhibitor HI-TOPK-032 Effectively Suppresses Colon Cancer Growth
Novel TOPK Inhibitor HI-TOPK-032 Effectively Suppresses Colon Cancer Growth
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DOI：
10.1158/0008-5472.can-11-3851
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发表时间：
2012-06-15
期刊：
影响因子：
11.2
通讯作者：
Dong, Zigang
中科院分区：
文献类型：
--
作者：
Kim, Dong Joon;Li, Yan;Dong, Zigang
丝-苏氨酸促分裂原活化蛋白激酶激酶家族成员T-LAK细胞来源的蛋白激酶（TOPK/PBK）在肿瘤发展、癌症生长、细胞凋亡和炎症中起重要作用。尽管TOPK被鉴定为有希望的新型治疗靶点，但尚未报道TOPK的抑制剂。在这项研究中，我们使用体外激酶试验筛选了36种候选药物，并鉴定了新型TOPK抑制剂HI-TOPK-032。在体外，HI-TOPK-032强烈抑制TOPK激酶活性，但对细胞外信号调节激酶1（ERK 1）、c-jun-NH 2-激酶1或p38激酶活性几乎没有影响。HI-TOPK-032还通过减少ERK-RSK磷酸化以及通过调节p53、裂解的半胱天冬酶-7和裂解的PARP的丰度增加结肠癌细胞凋亡来抑制贴壁依赖性和非贴壁依赖性结肠癌细胞生长。在体内，HI-TOPK-032的给药抑制了结肠癌异种移植模型中的肿瘤生长。因此，我们的研究结果表明，HI-TOPK-032在体外和体内都是TOPK的特异性抑制剂，可以进一步开发为针对结直肠癌的潜在治疗剂。Cancer Res; 72（12）; 3060-8.（C）2012年AACR。
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. (C)2012 AACR.