Abstract
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.
Highlights
The mitogen-activated protein kinase kinase (MAPKK) signaling pathway is a major component of the RAS/RAF/MEK/ ERK signaling axis
T-LAK cell–originated protein kinase (TOPK) is a serine-threonine kinase that is a member of MAPKK family and is involved in many cellular functions, including tumor development, cell growth, apoptosis, and inflammation [1,2,3,4,5]
We used in vitro kinase assays to investigate the effect of HI-TOPK-032 on other MAP. Kinase family members, such as extracellular signal–regulated kinase 1 (ERK1), JNK1, and p38 (Fig. 2C). These results showed that HI-TOPK-032 suppressed TOPK kinase activity, but not ERK1, JNK1, or p38 activity
Summary
The mitogen-activated protein kinase kinase (MAPKK) signaling pathway is a major component of the RAS/RAF/MEK/ ERK signaling axis. T-LAK cell–originated protein kinase (TOPK) is a serine-threonine kinase that is a member of MAPKK family and is involved in many cellular functions, including tumor development, cell growth, apoptosis, and inflammation [1,2,3,4,5]. It was reported to increase cell migration by modulating a PI3K/ PTEN/AKT-dependent signaling pathway [16]. These studies suggest that TOPK performs an oncogenic cellular function and its inhibition might be useful in cancer therapy, a TOPK inhibitor has not yet been identified. Our goal was to identify a novel TOPK inhibitor and to investigate its efficacy against colon cancer. We report that a novel compound, HI-TOPK-032, is a potent TOPK inhibitor that augments the efficacy of cancer treatment
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