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Combination of Aurora A and Haspin inhibitors enhances p53 expression and tumor growth inhibition in human colorectal cancer
Author(s) -
Chang YunHsuan,
Lin ChienI,
Chen ZanChu,
Liu KuangKai,
Chao JuiI
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.652.3
Subject(s) - survivin , aurora inhibitor , cancer research , apoptosis , colorectal cancer , mitosis , aurora a kinase , mitotic catastrophe , biology , cancer cell , cancer , cell growth , programmed cell death , cell cycle , microbiology and biotechnology , genetics
Colorectal cancer (CRC) is one of the leading causes and mortality in the world. Aurora A and Haspin are important mitotic kinases for promoting cancer progression. Here, we show the combination of an Aurora A inhibitor MLN8237 and a Haspin inhibitor CHR6494 that can enhance anticancer activities to CRC. Both MLN8237 and CHR6494 induced abnormal chromosome segregation and mitotic catastrophe. Interestingly, the combination of MLN8237 and CHR6494 enhanced the cell growth inhibition and apoptosis induction. Meantime, MLN8237 and CHR6494 reduced the protein levels of survivin. However, over‐expression of survivin by an ectopic survivin vector resisted the MLN8237 and CHR6494 induced cell death. Moreover, MLN8237 and CHR6494 induced higher apoptosis in the p53‐wild type cells than the p53‐null cells. MLN8237 and CHR6494 increased the total p53, phospho‐p53 (Ser46) and Bax for apoptosis induction. Combination of CHR6494 and MLN8237 enhanced the inhibition of xenografted human CRC tumors in nude mice. Together, these results demonstrate that targeting on Aurora A and Haspin by the inhibitors will be potentially developed as a novel strategy for CRC therapy.