Novel selective TOPK inhibitor SKLB-C05 inhibits colorectal carcinoma growth and metastasis
Novel selective TOPK inhibitor SKLB-C05 inhibits colorectal carcinoma growth and metastasis
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DOI：
10.1016/j.canlet.2018.12.016
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Yu, Luoting
中科院分区：
文献类型：
--
作者：
Gao, Tiantao;Hu, Quanfang;Yu, Luoting
丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号通路成员T-LAK细胞源性蛋白激酶/PDZ结合激酶（cell-originated protein kinase/PDZ-binding kinase，TOPK/PBK）与肿瘤的发生、发展密切相关。它在结直肠癌（CRC）中的过表达加重了肿瘤的恶性程度，促进了转移，并导致预后不良。因此，靶向TOPK是CRC治疗的一种有前途的方法。在这里，我们报告的开发TOPK选择性抑制剂SKLB-C 05，具有亚纳摩尔抑制效力。体外实验表明，SKLB-C 05对TOPIC高表达的结直肠癌细胞具有良好的细胞毒活性和抗迁移侵袭活性，并诱导细胞凋亡。这些活性可归因于其抑制TOPK下游信号传导，包括细胞外信号调节激酶1/2（ERK 1/2）、p38和c-Jun N-末端激酶1、2和3（JNK 1/2/3），以及下调FAK/Src-MMP信号传导。此外，SKLB-C 05破坏细胞有丝分裂并阻断CRC细胞周期。在体内，SKLB-C 05以20和10 mg/kg·day（-1）的浓度口服给药，分别显著减弱CRC肿瘤异种移植物生长和完全抑制HCT 116细胞的肝转移。因此，这些研究结果表明，SUB-COS是一种特异性TOPIC抑制剂，在体外和体内具有强效抗CRC致癌活性。
The mitogen-activated protein kinase (MAPK) signaling pathway member T-LAK cell-originated protein kinase/PDZ-binding kinase (TOPK/PBK) is closely involved in tumorigenesis and progression. Its overexpression in colorectal carcinoma (CRC) exacerbates tumor malignancy, promotes metastasis and results in dismal prognosis. Therefore, targeting TOPK is a promising approach for CRC therapy. Here, we report the development of a TOPK selective inhibitor SKLB-C05, with subnanomolar inhibitory potency. In vitro, SKLB-C05 exhibited excellent cytotoxicity and anti-migration and invasion activity on TOPIC high-expressing CRC cells and induced cell apoptosis. These activities could attribute to its inhibition of TOPK downstream signaling including extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun N-terminal kinase 1, 2, and 3 (JNK1/2/3), as well as downregulation of FAK/Src- MMP signaling. Furthermore, SKLB-C05 disrupted cell mitosis and blocked CRC cell cycle. In vivo, oral administration of SKLB-C05 at concentrations of 20 and 10 mg kg(-1).day(-1) dramatically attenuated CRC tumor xenograft growth and completely suppressed hepatic metastasis of HCT116 cells, respectively. Thus, these findings suggest that SUB-COS is a specific TOPIC inhibitor with potent anti-CRC oncogenic activity in vitro and in vivo.