Mitotic slippage and the subsequent cell fates after inhibition of Aurora B during tubulin-binding agent\u2013induced mitotic arrest

Yasuo Tsuda,Koji Ando,Yuichiro Nakashima,Kippei Ohgaki,Ryota Nakanishi,Makoto Iimori,Hiroshi Saeki,Eiji Oki,Yoshihiko Maehara,Hiroyuki Kitao

doi:10.1038/s41598-017-17002-z

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.

Highlights

Microtubules (MTs) are highly dynamic polymers that constantly switch between phases of growth and shrinkage[1,2,3]
Mitosis of HeLa cells was arrested on treatment with paclitaxel or eribulin, used at 100 nM and 10 nM, respectively, which are the minimum concentrations required for mitotic arrest (Supplementary Fig. 1), and chromosome segregation was inhibited by suppression of MT dynamics (Fig. 1A)
Breast cancer is divided into several subtypes according to the estrogen receptor (ER), progesterone receptor (PgR), and HER2 status, which are indicators for therapeutic strategy

Summary

Introduction

Microtubules (MTs) are highly dynamic polymers that constantly switch between phases of growth and shrinkage[1,2,3]. TBAs are mainly classified into MT-stabilizing and MT-destabilizing agents The former is exemplified by taxans and epothilones, and the latter, by vinca alkaloids, vinorelbine, and eribulin, which is a synthetic analogue of halichondrin B, is the newest anti-tumor drug for breast cancer by inhibiting MT polymerization irreversibly. Both kinds of TBAs suppress MT dynamics and induce mitotic arrest identically, these agents affect MT dynamics in completely different ways. A comparison of mitotic cell response, including mitotic slippage, and postmitotic cell fates following paclitaxel and eribulin treatment when Aurora B is inhibited may help to select drugs for the clinical treatment of breast cancer

Methods

Results

Conclusion