Mitotic slippage and the subsequent cell fates after inhibition of Aurora B during tubulin-binding agent–induced mitotic arrest

Abstract

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.

Amentoflavone triggers cell cycle G2/M arrest by interfering with microtubule dynamics and inducing DNA damage in SKOV3 cells

“…In the present study, the expression levels of p-CDK1 and CDK2 significantly decreased, while P21 expression increased in AMF-treated SKOV3 cells, suggesting that AMF may induce G 2 /M cell cycle arrest by upregulating P21 and downregulating CDK1 and CDK2. A previous study demonstrated that paclitaxel or eribulin can arrest cell meiosis and lead to the accumulation of mitotic marker proteins, such as cyclin B1 (42). In the present study, cyclin B1 was significantly downregulated following treatment with 100 µmol/l AMF, but upregulated following treatment with 150 µmol/l AMF.…”

The interplay between TGF‐β‐stimulated TSC22 domain family proteins regulates cell‐cycle dynamics in medulloblastoma cells

“…We confirmed that these cells are committed to apoptosis by showing that this fraction perfectly matched that of Annexin V-positive cells upon exposure to staurosporine and ruling out the possibility that they were induced to senescence. The specific increase of apoptotic cells is also consistent with the significant reduction of the G2/M phase cell fraction, which likely indicates that the abrogation of TSC22D1.1 promotes mitotic slippage and subsequent apoptosis (Castedo et al, 2004;Tsuda et al, 2017;Vakifahmetoglu, Olsson, & Zhivotovsky, 2008). Therefore, the long TSC22D1.1 isoform appears to act as a major proliferationfavoring factor, either alone or interacting with other factors still to be identified.…”

The origins and functions of hepatic polyploidy

“…Thereby, cells undergoing "mitotic slippage", also referred to as "postmitotic" cells, become polyploid. Tubulin binding agents such as taxanes, epothilones, and vinca alkaloids can activate the SAC to induce mitotic slippage [39,40]. However, how cells choose between "mitotic catastrophe" or "mitotic slippage" is still unclear [41,42].…”