Kato Taigo, Inoue Hiroyuki, Imoto Seiya, Tamada Yoshinori, Miyamoto Takashi, Matsuo Yo, Nakamura Yusuke, Park Jae-Hyun
Department of Medicine, The University of Chicago, Chicago, IL, USA.
Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Oncotarget. 2016 Apr 5;7(14):17652-64. doi: 10.18632/oncotarget.7755.
T-lymphokine-activated killer cell-originated protein kinase (TOPK) and maternal embryonic leucine zipper kinase (MELK) have been reported to play critical roles in cancer cell proliferation and maintenance of stemness. In this study, we investigated possible roles of TOPK and MELK in kidney cancer cells and found their growth promotive effect as well as some feedback mechanism between these two molecules. Interestingly, the blockade of either of these two kinases effectively caused downregulation of forkhead box protein M1 (FOXM1) activity which is known as an oncogenic transcriptional factor in various types of cancer cells. Small molecular compound inhibitors against TOPK (OTS514) and MELK (OTS167) effectively suppressed the kidney cancer cell growth, and the combination of these two compounds additively worked and showed the very strong growth suppressive effect on kidney cancer cells. Collectively, our results suggest that both TOPK and MELK are promising molecular targets for kidney cancer treatment and that dual blockade of OTS514 and OTS167 may bring additive anti-tumor effects with low risk of side effects.
据报道，T淋巴细胞激活的杀伤细胞源蛋白激酶（TOPK）和母体胚胎亮氨酸拉链激酶（MELK）在癌细胞增殖和干性维持中发挥关键作用。在本研究中，我们调查了TOPK和MELK在肾癌细胞中的可能作用，发现它们具有促进生长的作用以及这两种分子之间的一些反馈机制。有趣的是，这两种激酶中的任何一种被阻断都会有效导致叉头框蛋白M1（FOXM1）活性下调，而FOXM1在各种类型的癌细胞中是一种致癌转录因子。针对TOPK（OTS514）和MELK（OTS167）的小分子化合物抑制剂有效抑制肾癌细胞生长，这两种化合物联合使用具有累加作用，对肾癌细胞显示出非常强的生长抑制作用。总体而言，我们的结果表明，TOPK和MELK都是肾癌治疗有前景的分子靶点，OTS514和OTS167的双重阻断可能带来累加的抗肿瘤作用且副作用风险较低。
