抄録
Tubulin-binding agents (TBAs) are designed to target microtubule (MT) dynamics, resulting in compromised mitotic spindles and an unsatisfied spindle assembly checkpoint. The activity of Aurora B kinase is indispensable for TBA-induced mitotic arrest, and its inhibition causes mitotic slippage and postmitotic endoreduplication. However, the precise phenomenon underlying mitotic slippage, which is caused by treatment with both Aurora B inhibitors and TBAs, and the cell fate after postmitotic slippage are not completely understood. Here, we found that HeLa and breast cancer cells treated with the different types of TBAs, such as paclitaxel and eribulin (MT-stabilizing and MT-destabilizing agents, respectively), exhibited distinct behaviors of mitotic slippage on inhibition of Aurora B. In such conditions, the cell fates after postmitotic slippage vastly differed with respect to cell morphology, cell proliferation, and cytotoxicity in short-term culture; that is, the effects of inhibition of Aurora B were beneficial for cytotoxicity enhancement in eribulin treatment but not in paclitaxel. However, in long-term culture, the cells that survived after mitotic slippage underwent endoreduplication and became giant cells in both cases, resulting in cellular senescence. We propose that MT-destabilizing agents may be more appropriate than MT-stabilizing agents for treating cancer cells with a weakened Aurora B kinase activity.
| 元の言語 | 英語 |
|---|---|
| 記事番号 | 16762 |
| ジャーナル | Scientific reports |
| 巻 | 7 |
| 発行部数 | 1 |
| DOI | |
| 出版物ステータス | 出版済み - 12 1 2017 |
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All Science Journal Classification (ASJC) codes
- General
これを引用
Mitotic slippage and the subsequent cell fates after inhibition of Aurora B during tubulin-binding agent-induced mitotic arrest. / Tsuda, Yasuo; Iimori, Makoto; Nakashima, Yuichiro; Nakanishi, Ryota; Ando, Koji; Ohgaki, Kippei; Kitao, Hiroyuki; Saeki, Hiroshi; Oki, Eiji; Maehara, Yoshihiko.
：: Scientific reports, 巻 7, 番号 1, 16762, 01.12.2017.研究成果: ジャーナルへの寄稿 › 記事
}
TY - JOUR
T1 - Mitotic slippage and the subsequent cell fates after inhibition of Aurora B during tubulin-binding agent-induced mitotic arrest
AU - Tsuda, Yasuo
AU - Iimori, Makoto
AU - Nakashima, Yuichiro
AU - Nakanishi, Ryota
AU - Ando, Koji
AU - Ohgaki, Kippei
AU - Kitao, Hiroyuki
AU - Saeki, Hiroshi
AU - Oki, Eiji
AU - Maehara, Yoshihiko
PY - 2017/12/1
Y1 - 2017/12/1
N2 - Tubulin-binding agents (TBAs) are designed to target microtubule (MT) dynamics, resulting in compromised mitotic spindles and an unsatisfied spindle assembly checkpoint. The activity of Aurora B kinase is indispensable for TBA-induced mitotic arrest, and its inhibition causes mitotic slippage and postmitotic endoreduplication. However, the precise phenomenon underlying mitotic slippage, which is caused by treatment with both Aurora B inhibitors and TBAs, and the cell fate after postmitotic slippage are not completely understood. Here, we found that HeLa and breast cancer cells treated with the different types of TBAs, such as paclitaxel and eribulin (MT-stabilizing and MT-destabilizing agents, respectively), exhibited distinct behaviors of mitotic slippage on inhibition of Aurora B. In such conditions, the cell fates after postmitotic slippage vastly differed with respect to cell morphology, cell proliferation, and cytotoxicity in short-term culture; that is, the effects of inhibition of Aurora B were beneficial for cytotoxicity enhancement in eribulin treatment but not in paclitaxel. However, in long-term culture, the cells that survived after mitotic slippage underwent endoreduplication and became giant cells in both cases, resulting in cellular senescence. We propose that MT-destabilizing agents may be more appropriate than MT-stabilizing agents for treating cancer cells with a weakened Aurora B kinase activity.
AB - Tubulin-binding agents (TBAs) are designed to target microtubule (MT) dynamics, resulting in compromised mitotic spindles and an unsatisfied spindle assembly checkpoint. The activity of Aurora B kinase is indispensable for TBA-induced mitotic arrest, and its inhibition causes mitotic slippage and postmitotic endoreduplication. However, the precise phenomenon underlying mitotic slippage, which is caused by treatment with both Aurora B inhibitors and TBAs, and the cell fate after postmitotic slippage are not completely understood. Here, we found that HeLa and breast cancer cells treated with the different types of TBAs, such as paclitaxel and eribulin (MT-stabilizing and MT-destabilizing agents, respectively), exhibited distinct behaviors of mitotic slippage on inhibition of Aurora B. In such conditions, the cell fates after postmitotic slippage vastly differed with respect to cell morphology, cell proliferation, and cytotoxicity in short-term culture; that is, the effects of inhibition of Aurora B were beneficial for cytotoxicity enhancement in eribulin treatment but not in paclitaxel. However, in long-term culture, the cells that survived after mitotic slippage underwent endoreduplication and became giant cells in both cases, resulting in cellular senescence. We propose that MT-destabilizing agents may be more appropriate than MT-stabilizing agents for treating cancer cells with a weakened Aurora B kinase activity.
UR - http://www.scopus.com/inward/record.url?scp=85036667247&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85036667247&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-17002-z
DO - 10.1038/s41598-017-17002-z
M3 - Article
C2 - 29196757
AN - SCOPUS:85036667247
VL - 7
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 16762
ER -