Combination Treatment of OSI-906 with Aurora B Inhibitor Reduces Cell Viability via Cyclin B1 Degradation-Induced Mitotic Slippage
| Autor: | Yuji Nakayama, Youhei Saito, Ryuzaburo Yuki, Yuki Ikeda, Ryuji Yasutake |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Lung Neoplasms
Cell division linsitinib Cell Survival QH301-705.5 Aurora B kinase Mitosis Catalysis Article Receptor IGF Type 1 Inorganic Chemistry chemistry.chemical_compound IGF1R Cell Line Tumor Aurora Kinase B Humans Viability assay Physical and Theoretical Chemistry Cyclin B1 Aurora B Biology (General) Molecular Biology Protein Kinase Inhibitors QD1-999 Spectroscopy Cell Proliferation Dose-Response Relationship Drug Chemistry Cell growth Organic Chemistry Cell Cycle Imidazoles General Medicine Computer Science Applications ZM447439 Cell biology Spindle checkpoint OSI-906 Pyrazines Benzamides Proteolysis Quinazolines M phase Cytokinesis RO-3306 |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 5706, p 5706 (2021) International Journal of Molecular Sciences Volume 22 Issue 11 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | Insulin-like growth factor 1 receptor (IGF1R), a receptor-type tyrosine kinase, transduces signals related to cell proliferation, survival, and differentiation. We recently reported that OSI-906, an IGF1R inhibitor, in combination with the Aurora B inhibitor ZM447439 suppresses cell proliferation. However, the mechanism underlying this suppressive effect is yet to be elucidated. In this study, we examined the effects of combination treatment with OSI-906 and ZM447439 on cell division, so as to understand how cell proliferation was suppressed. Morphological analysis showed that the combination treatment generated enlarged cells with aberrant nuclei, whereas neither OSI-906 nor ZM447439 treatment alone caused this morphological change. Flow cytometry analysis indicated that over-replicated cells were generated by the combination treatment, but not by the lone treatment with either inhibitors. Time-lapse imaging showed mitotic slippage following a severe delay in chromosome alignment and cytokinesis failure with furrow regression. Furthermore, in S-trityl-l-cysteine–treated cells, cyclin B1 was precociously degraded. These results suggest that the combination treatment caused severe defect in the chromosome alignment and spindle assembly checkpoint, which resulted in the generation of over-replicated cells. The generation of over-replicated cells with massive aneuploidy may be the cause of reduction of cell viability and cell death. This study provides new possibilities of cancer chemotherapy. |
| Databáze: | OpenAIRE |
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