| Summary: | 碩士 === 國立交通大學 === 分子醫學與生物工程研究所 === 102 === The phosphorylation of histone 3 and the chromosomal passenger complex (CPC), composed of Aurora B, survivin, INCENP and borealin, have been indicated important roles on the control of mitotic spindle and chromosomal segregation. Aurora A and haspin are mitotic kinases that can regulate mitotic progression. However, the roles of Aurora A and haspin on the phosphorylation of histone 3 and the formation of CPC remain largely unclear. Colorectal cancer (CRC) is one of the leading causes and mortality in the world. In this study, we investigated the roles of Aurora A and haspin on the regulation of histone 3 and CPC using CRC model. Both MLN8237 (an Aurora A inhibitor) and CHR6494 (a haspin inhibitor) induced centrosomal amplification, spindle multi-polarity and mitotic catastrophe in CRC cells. Interestingly, the combination of MLN8237 and CHR6494 enhanced the anticancer abilities, including the cell viability reduction, polyploidy cells increase, growth inhibition and apoptosis induction. Meantime, MLN8237 and CHR6494 inhibited the protein phosphorylations of histone 3 at Thr-3 and Ser-10 and the protein levels of Aurora B and survivin. Over-expression of survivin by pCT-GFP-sur8 vector could reduce the MLN8237 or CHR6494 induced cell death. This report demonstrates for the first time that Aurora A and haspin can co-regulate the phosphorylation of histone 3 and the formation of CPC. The combined targeting drugs on Aurora A and haspin may develop a novel strategy for CRC therapy.
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