Abstract
T-cell-originated protein kinase (TOPK) is highly and frequently expressed in various cancer tissues and plays an indispensable role in the mitosis of cancer cells, and therefore, it is an important target for drug treatment of tumor. Ilaprazole was identified to be a potent TOPK inhibitor. The data indicated that ilaprazole inhibited TOPK activities with high affinity and selectivity. In vitro studies showed that ilaprazole inhibited TOPK activities in HCT116, ES-2, A549, SW1990 cancer cells. Moreover, knockdown of TOPK in these cells decreased their sensitivities to ilaprazole. Results of an in vivo study demonstrated that gavage of ilaprazole in HCT116 colon tumor-bearing mice effectively suppressed cancer growth. The TOPK downstream signaling molecule phospho-histone H3 in tumor tissues was also decreased after ilaprazole treatment. Our results suggested that ilaprazole inhibited the cancer growth by targeting TOPK both in vitro and in vivo.
Highlights
T-cell-originated protein kinase (TOPK) (T-lymphokine-activated killer cell-originated protein kinase) is a Ser/Thr protein kinase, known as PBK or PDZ-binding kinase, which belongs to the MEK protein family [1, 2]
The homology model of human TOPK was constructed by using the X-ray structure of the mixed-lineage kinase MLK1 (PDB code: 3DTC) as the template, which has 29% of sequence identities to the human TOPK
Many groups have reported that TOPK was associated with oncogenic cellular functions including tumor development, cancer growth, and anti-apoptotic effects [1,2, 7,8,9]
Summary
TOPK (T-lymphokine-activated killer cell-originated protein kinase) is a Ser/Thr protein kinase, known as PBK or PDZ-binding kinase, which belongs to the MEK protein family [1, 2]. TOPK was reported to increase cell migration by modulating a PI3K/ PTEN/AKT-dependent signaling pathway [8]. Histone H3 could be phosphorylated at Ser by TOPK both in vivo and in vitro, which could mediate cell growthpromoting effects [9]. Based on these findings, TOPK has become a novel target for cancer treatment attracting more and more attentions [10]. None of them had been in clinical trials because of their toxicities or poor pharmacokinetic properties
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