TC Mps1 12, a novel Mps1 inhibitor, suppresses the growth of hepatocellular carcinoma cells via the accumulation of chromosomal instability

Abstract

contributed equally to the work. BACKGROUND AND PURPOSEChromosomal instability is not only a hallmark of cancer but also an attractive therapeutic target. A diverse set of mitotic kinases maintains chromosomal stability. One of these is monopolar spindle 1 (Mps1, also known as TTK), which is essential for chromosome alignment and for the spindle assembly checkpoint (SAC). Pharmacological inhibition of Mps1 has been suggested as a cancer therapeutic; however, despite the existence of a novel Mps1 inhibitor, TC Mps1 12, no such studies have been performed. EXPERIMENTAL APPROACHThe effects of TC Mps1 12 on cell viability, chromosome alignment, centrosome number, mitotic duration, apoptosis and SAC were determined in hepatocellular carcinoma (HCC) cells. In addition, the association of Mps1 expression with the overall survival of HCC patients was analysed. KEY RESULTSTreatment of human HCC cells with TC Mps1 12 led to chromosome misalignment and missegregation, and disorganization of centrosomes. Even in the presence of these errors, TC Mps1 12-treated cells overrode the SAC, resulting in a shortened mitotic duration and mitotic slippage. This mitotic catastrophe triggered apoptosis and, finally, inhibited the growth of HCC cells. In addition, the expression of the Mps1-encoding TTK gene was associated with poor overall survival of HCC patients. CONCLUSION AND IMPLICATIONSTC Mps1 12 results in the accumulation of chromosomal instabilities and mitotic catastrophe in HCC cells. Overall, these data demonstrate that the inhibition of Mps1 kinase using TC Mps1 12 is a promising therapeutic approach for liver cancer.Abbreviations HCC, hepatocellular carcinoma; MCC, mitotic checkpoint complex; Mps1 (TTK), monopolar spindle 1; SAC, spindle assembly checkpoint

Integrated genomics and comprehensive validation reveal novel drivers of genomic evolution in esophageal adenocarcinoma

“…This is consistent with our other observations showing that transgenic suppression of TTK in EAC cells, inhibits spontaneous DNA damage and HR activity, whereas transgenic overexpression of TTK in normal esophageal epithelial cells increases spontaneous DNA damage, HR activity and genomic instability as assessed by whole genome SNP arrays and sequencing. However, the difference between our data and that from other cancers 35,39 could also be attributed to different mechanisms operative in these cancers. Moreover, the role of TTK in prostate cancer progression 40 is also consistent with our data demonstrating that TTK overexpression dysregulates HR and genome stability in EAC cells.…”

“…TTK has been identified as one of the promising candidates for vaccination in esophageal cancer patients with advanced stage disease 33,34 . Role of TTK in survival of cancer cells and cytotoxicity of its inhibitors has also been demonstrated in hepatocellular carcinoma 35 and glioblastoma 36 .…”

“…Evidence from pancreatic and breast cancers suggests that the mechanism of cell death following treatment with TTK inhibitors is induction of genomic instability 35,39 . This seems to be in contradiction with our results in EAC showing that treatment with TTK inhibitor reduces spontaneous DNA damage and genomic instability.…”

Inhibition of kinesin family member 20B sensitizes hepatocellular carcinoma cell to microtubule‐targeting agents by blocking cytokinesis

“…Great efforts have been made to unveil the mechanisms underlying the insensitivity of HCC cells to chemotherapies, such as MTA . One main cause that confers MTA resistance to HCC cells is the mitotic checkpoint bypass . For example, the regulation of SAC, which controls cell cycle progression during mitosis and synchronizes mitosis by attaching chromosomes to spindle microtubules, is critical for taxol‐mediated cell death .…”

“…3,4 One main cause that confers MTA resistance to HCC cells is the mitotic checkpoint bypass. 5 For example, the regulation of SAC, which controls cell cycle progression during mitosis and synchronizes mitosis by attaching chromosomes to spindle microtubules, 6 is critical for taxol-mediated cell death. 7,8 However, reduced or malfunctioned SAC is commonly seen in cancer cells, 9 and such SAC defects usually correlate with MTA resistance.…”