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Inhibition of Aurora-B function increases formation of multinucleated cells in p53 gene deficient cells and enhances anti-tumor effect of temozolomide in human glioma cells

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Abstract

Cell division is an elemental process, and mainly consists of chromosome segregation and subsequent cytokinesis. Some errors in this process have the possibility of leading to carcinogenesis. Aurora-B is known as a chromosomal passenger protein that regulates cell division. In our previous studies of giant cell glioblastoma, we reported that multinucleated giant cells resulted from aberrations in cytokinesis with intact nuclear division occurring in the early mitotic phase, probably due to Aurora-B dysfunction. In this study, as we determined p53 gene mutation occurring in multinucleated giant cell glioblastoma, we investigated the role of Aurora-B in formation of multinucleated cells in human neoplasm cells with various p53 statuses as well as cytotoxity of glioma cells to temozolomide (TMZ), a common oral alkylating agent used in the treatment of gliomas. The inhibition of Aurora-B function by small-interfering (si)RNA led to an increase in the number of multinucleated cells and the ratios of G2/M phase in p53-mutant and p53-null cells, but not in p53-wild cells or the cells transduced adenovirally with wild-p53. The combination of TMZ and Aurora-B-siRNA remarkably inhibited the cell viability of TMZ-resistant glioma cells. Accordingly, our results suggested that Aurora-B dysfunction increases in the appearance of multinucleated cells in p53 gene deficient cells, and TMZ treatment in combination with the inhibition of Aurora-B function may become a potential therapy against p53 gene deficient and chemotherapeutic-resistant human gliomas.

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Acknowledgements

We thank Professor Hirofumi Hamada, Department of Molecular Medicine, Sapporo Medical University, for providing adenoviral vectors. This manuscript was supported in part by Grants-in-Aid for Scientific Research 16209044 and 16390408 from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Neurosurgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan

    Takaya Tsuno, Atsushi Natsume, Shun Katsumata, Masaaki Mizuno, Mitsugu Fujita, Hirokatsu Osawa, Norimoto Nakahara, Toshihiko Wakabayashi, Yu-ichiro Satoh & Jun Yoshida

  2. Center for Genetic and Regenerative Medicine, Nagoya University Hospital, Nagoya, Aichi, Japan

    Atsushi Natsume, Toshihiko Wakabayashi & Jun Yoshida

  3. Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya, Aichi, Japan

    Masaki Inagaki

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  1. Takaya Tsuno
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Correspondence to Jun Yoshida.

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Tsuno, T., Natsume, A., Katsumata, S. et al. Inhibition of Aurora-B function increases formation of multinucleated cells in p53 gene deficient cells and enhances anti-tumor effect of temozolomide in human glioma cells. J Neurooncol 83, 249–258 (2007). https://doi.org/10.1007/s11060-007-9335-1

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