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

Kwang Woon Kim, Robert Mutter, Christopher D. Willey, Ty K. Subhawong, Eric T. Shinohara, Jeffrey M. Albert, Geng Ling, Carolyn Cao, Young Jin Gi, Bo Lu

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1519-1525
Number of pages7
JournalInternational Journal of Radiation Oncology Biology Physics
Volume67
Issue number5
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

Fingerprint

Aurora Kinase B
Mesothelioma
cells
irradiation
oligonucleotides
Antisense Oligonucleotides
inhibitors
Caspase 10
proteins
mitosis
molecules
cytometry
passengers
augmentation
Centromere
G2 Phase
Radiation Tolerance
chromosomes
apoptosis
radiation tolerance

Keywords

  • Aurora B kinase
  • Mesothelioma
  • Radiation
  • Survivin
  • ZM447439

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

Inhibition of Survivin and Aurora B Kinase Sensitizes Mesothelioma Cells by Enhancing Mitotic Arrests. / Kim, Kwang Woon; Mutter, Robert; Willey, Christopher D.; Subhawong, Ty K.; Shinohara, Eric T.; Albert, Jeffrey M.; Ling, Geng; Cao, Carolyn; Gi, Young Jin; Lu, Bo.

In: International Journal of Radiation Oncology Biology Physics, Vol. 67, No. 5, 01.04.2007, p. 1519-1525.

Research output: Contribution to journalArticle

Kim, Kwang Woon ; Mutter, Robert ; Willey, Christopher D. ; Subhawong, Ty K. ; Shinohara, Eric T. ; Albert, Jeffrey M. ; Ling, Geng ; Cao, Carolyn ; Gi, Young Jin ; Lu, Bo. / Inhibition of Survivin and Aurora B Kinase Sensitizes Mesothelioma Cells by Enhancing Mitotic Arrests. In: International Journal of Radiation Oncology Biology Physics. 2007 ; Vol. 67, No. 5. pp. 1519-1525.
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AU - Kim, Kwang Woon

AU - Mutter, Robert

AU - Willey, Christopher D.

AU - Subhawong, Ty K.

AU - Shinohara, Eric T.

AU - Albert, Jeffrey M.

AU - Ling, Geng

AU - Cao, Carolyn

AU - Gi, Young Jin

AU - Lu, Bo

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N2 - 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.

AB - 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.

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