Inhibition of Survivin and Aurora B Kinase Sensitizes Mesothelioma Cells by Enhancing Mitotic Arrests

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• 作者：Kwang Woon Kim ; Robert W. Mutter ; Christopher D. Willey ; Ty K. Subhawong ; Eric T. Shinohara ; Jeffrey M. Albert ; Geng Ling ; Carolyn Cao ; Young Jin Gi ; Bo Lu
• 关键词：Survivin ; Aurora B kinase ; Mesothelioma ; Radiation ; ZM447439
• 刊名：International Journal of Radiation Oncology*Biology*Physics
• 出版年：2007
• 出版时间：1 April 2007
• 年：2007
• 卷：67
• 期：5
• 页码：1519-1525
• 全文大小：381 K

文摘

Purpose: Survivin, a member of the inhibitor of apoptosis gene family, has also been shown to regulate mitosis. It binds Aurora B kinase and the inner centromere protein to form the chromosome passenger complex. Both Aurora B and survivin are overexpressed in many tumors. In this study, we examined whether irradiation affected survivin and Aurora B expression in mesothelioma cells, and how inhibition of these molecules affected radiosensitivity.

Methods and Materials: ZM447439 and survivin antisense oligonucleotides were used to inhibit survivin and Aurora B kinase respectively. Western blot was performed to determine the expression of survivin, Aurora B, phosphorylated-histone H3 (Ser 10), and caspase cleavage. Multinucleated cells were counted using flow cytometry, and cell survival after treatment was determined using clonogenic assay.

Results: At 3-Gy irradiation an increase was observed in levels of survivin and Aurora B as well as the kinase activity of Aurora B, with an increase in G2/M phase. The radiation-induced upregulation of these molecules was effectively attenuated by antisense oligonucleotides against survivin and a small-molecule inhibitor of Aurora B, ZM447439. Dual inhibition of survivin and Aurora B synergistically radiosensitized mesothelioma cells with a dose enhancement ratio of 2.55. This treatment resulted in increased formation of multinucleated cells after irradiation but did not increase levels of cleaved caspase 3.

Conclusion: Inhibition of survivin and Aurora B induces mitotic cell arrest in mesothelioma cells after irradiation. These two proteins may be potential therapeutic targets for the enhancement of radiotherapy in malignant pleural mesothelioma.