ATP depletion during mitotic arrest induces mitotic slippage and APC/CCdh1-dependent cyclin B1 degradation

Abstract

ATP depletion inhibits cell cycle progression, especially during the G1 phase and the G2 to M transition. However, the effect of ATP depletion on mitotic progression remains unclear. We observed that the reduction of ATP after prometaphase by simultaneous treatment with 2-deoxyglucose and NaN3 did not arrest mitotic progression. Interestingly, ATP depletion during nocodazole-induced prometaphase arrest resulted in mitotic slippage, as indicated by a reduction in mitotic cells, APC/C-dependent degradation of cyclin B1, increased cell attachment, and increased nuclear membrane reassembly. Additionally, cells successfully progressed through the cell cycle after mitotic slippage, as indicated by EdU incorporation and time-lapse imaging. Although degradation of cyclin B during normal mitotic progression is primarily regulated by APC/CCdc20, we observed an unexpected decrease in Cdc20 prior to degradation of cyclin B during mitotic slippage. This decrease in Cdc20 was followed by a change in the binding partner preference of APC/C from Cdc20 to Cdh1; consequently, APC/CCdh1, but not APC/CCdc20, facilitated cyclin B degradation following ATP depletion. Pulse-chase analysis revealed that ATP depletion significantly abrogated global translation, including the translation of Cdc20 and Cdh1. Additionally, the half-life of Cdh1 was much longer than that of Cdc20. These data suggest that ATP depletion during mitotic arrest induces mitotic slippage facilitated by APC/CCdh1-dependent cyclin B degradation, which follows a decrease in Cdc20 resulting from reduced global translation and the differences in the half-lives of the Cdc20 and Cdh1 proteins.

Heat shock‐induced mitotic arrest requires heat shock protein 105 for the activation of spindle assembly checkpoint

“…Consistent with this, mitotic slippage was induced when taxol-treated cells were exposed to heat shock (61), implying that heat shock can attenuate SAC activation. Very recently, it was reported that ATP depletion induces mitotic slippage via APC/C-dependent cyclin B1 degradation (62). Given that ATP levels are reduced during heat stress (16,58,59), heat shock-induced attenuation of the 0.01 mg/ml taxol for 24 h and monitored by time-lapse imaging during the second half of the taxol treatment.…”

Discovery of Novel Agents on Spindle Assembly Checkpoint to Sensitize Vinorelbine-Induced Mitotic Cell Death against Human Non-Small Cell Lung Cancers

“…Notably, mitotic slippage may occur prematurely without accurate chromosomal segregation or cytokinesis [39]. The rate of mitotic slippage is positively correlated to the rate of cyclin B1 ubiquitination and degradation in active SAC condition [40,41]. Numerous studies have documented that mitotic slippage can limit the effectiveness of microtubule poisons [42].…”

Genomic heterogeneity meets cellular energetics: crosstalk between the mitochondria and the cell cycle

“…In turn, Drp1 promotes mitotic exit (adaptation) of cells arrested in mitosis with the microtubule-stabilizing drug taxol via regulation of Cyclin B1 levels [78] . Similarly, ATP depletion by addition of 2-deoxy-glucose (2-DG) and sodium azide promotes mitotic exit in cells arrested in mitosis with the microtubule depolymerizing drug nocodazole, and this adaptation is also due to reduction in Cyclin B levels [79] . These results indicate a bi-directional crosstalk where the mitotic machinery increases Drp1 activity and mitochondria dynamics in mitosis, which in turn feedbacks to regulate mitosis [80] .…”

“…Other metabolic alterations such as starvation and the subsequent induction of autophagy, or hypoxia have also been shown to regulate cell cycle progression [97] . Mitochondria dynamics/function have a role in the regulation of mitosis since Drp1 activity and ATP depletion promote mitotic exit in cells arrested in mitosis with microtubule-targeting drugs [78,79] . This exit from mitotic arrest when mitochondria function is compromised is due to premature degradation of Cyclin B1 by activation of the ubiquitin ligase APC/C Cdh1 [79] .…”

“…Mitochondria dynamics/function have a role in the regulation of mitosis since Drp1 activity and ATP depletion promote mitotic exit in cells arrested in mitosis with microtubule-targeting drugs [78,79] . This exit from mitotic arrest when mitochondria function is compromised is due to premature degradation of Cyclin B1 by activation of the ubiquitin ligase APC/C Cdh1 [79] . These results indicate a complex cross-talk between mitochondria functions and the mitotic machinery, which has important implications for our understanding of the response of cancer cells to microtubule-targeting agents commonly used as cancer treatments (e.g., taxol, vinblastine).…”