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.

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.

• Authors: Takaya Tsuno, Atsushi Natsume, Shun Katsumata, Masaaki Mizuno, Mitsugu Fujita, Hirokatsu Osawa, Norimoto Nakahara, Toshihiko Wakabayashi, Yu-ichiro Satoh, Masaki Inagaki, Jun Yoshida
• Journal: Journal of neuro-oncology (J Neurooncol) Vol. 83 Issue 3 Pg. 249-58 (Jul 2007) ISSN: 0167-594X [Print] United States
• PMID: 17570035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• RNA, Small Interfering
• Tumor Suppressor Protein p53
• Dacarbazine
• AURKB protein, human
• Aurora Kinase B
• Aurora Kinases
• Protein Serine-Threonine Kinases
• Temozolomide

Topics

• Antineoplastic Agents, Alkylating (therapeutic use)
• Aurora Kinase B
• Aurora Kinases
• Blotting, Western
• Brain Neoplasms (drug therapy, genetics, pathology)
• Cell Cycle (drug effects)
• Cell Survival (drug effects)
• Dacarbazine (analogs & derivatives, therapeutic use)
• Flow Cytometry
• Giant Cells (pathology)
• Glioma (drug therapy, genetics, pathology)
• Humans
• Mutation (genetics)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• RNA, Small Interfering (pharmacology)
• Temozolomide
• Tumor Cells, Cultured (drug effects)
• Tumor Suppressor Protein p53 (genetics, metabolism)