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

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 multinucleatedmore » 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.« less

Authors:
 [1];  [1];  [1];  [2];  [3];  [1];  [1];  [1];  [4];  [5]
  1. Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN (United States)
  2. Department of Radiation Oncology, University of Pennsylvania Health System, Philadelphia, PA (United States)
  3. Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD (United States)
  4. Department of Surgical Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN (United States)
  5. Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN (United States). E-mail: bo.lu@vanderbilt.edu
Publication Date:
OSTI Identifier:
20951600
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 67; Journal Issue: 5; Other Information: DOI: 10.1016/j.ijrobp.2006.12.018; PII: S0360-3016(06)03665-0; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
63 RADIATION, THERMAL, AND OTHER ENVIRONMENTAL POLLUTANT EFFECTS ON LIVING ORGANISMS AND BIOLOGICAL MATERIALS; APOPTOSIS; CENTROMERES; CHROMOSOMES; DOSES; GENES; INHIBITION; IRRADIATION; MITOSIS; NEOPLASMS; OLIGONUCLEOTIDES; PROTEINS; RADIOSENSITIVITY; RADIOTHERAPY

Citation Formats

Kim, Kwang Woon, Mutter, Robert W., Willey, Christopher D., Subhawong, Ty K., Shinohara, Eric T., Albert, Jeffrey M., Ling Geng, Cao, Carolyn, Gi, Young Jin, and Bo Lu. Inhibition of Survivin and Aurora B Kinase Sensitizes Mesothelioma Cells by Enhancing Mitotic Arrests. United States: N. p., 2007. Web. doi:10.1016/j.ijrobp.2006.12.018.
Kim, Kwang Woon, Mutter, Robert W., Willey, Christopher D., Subhawong, Ty K., Shinohara, Eric T., Albert, Jeffrey M., Ling Geng, Cao, Carolyn, Gi, Young Jin, & Bo Lu. Inhibition of Survivin and Aurora B Kinase Sensitizes Mesothelioma Cells by Enhancing Mitotic Arrests. United States. doi:10.1016/j.ijrobp.2006.12.018.
Kim, Kwang Woon, Mutter, Robert W., Willey, Christopher D., Subhawong, Ty K., Shinohara, Eric T., Albert, Jeffrey M., Ling Geng, Cao, Carolyn, Gi, Young Jin, and Bo Lu. Sun . "Inhibition of Survivin and Aurora B Kinase Sensitizes Mesothelioma Cells by Enhancing Mitotic Arrests". United States. doi:10.1016/j.ijrobp.2006.12.018.
@article{osti_20951600,
title = {Inhibition of Survivin and Aurora B Kinase Sensitizes Mesothelioma Cells by Enhancing Mitotic Arrests},
author = {Kim, Kwang Woon and Mutter, Robert W. and Willey, Christopher D. and Subhawong, Ty K. and Shinohara, Eric T. and Albert, Jeffrey M. and Ling Geng and Cao, Carolyn and Gi, Young Jin and Bo Lu},
abstractNote = {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.},
doi = {10.1016/j.ijrobp.2006.12.018},
journal = {International Journal of Radiation Oncology, Biology and Physics},
number = 5,
volume = 67,
place = {United States},
year = {Sun Apr 01 00:00:00 EDT 2007},
month = {Sun Apr 01 00:00:00 EDT 2007}
}