scholarly journals BubR1 Is Essential for Thio-Dimethylarsinic Acid-Induced Spindle Assembly Checkpoint and Mitotic Cell Death for Preventing the Accumulation of Abnormal Cells

2019 ◽  
Vol 42 (7) ◽  
pp. 1089-1097 ◽  
Author(s):  
Kayoko Kita ◽  
Yu Imai ◽  
Nanami Asaka ◽  
Toshihide Suzuki ◽  
Takafumi Ochi
Keyword(s):  
Cell Death ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Cell ◽  
Dimethylarsinic Acid ◽  
Abnormal Cells

scholarly journals Antagonizing the spindle assembly checkpoint silencing enhances paclitaxel and Navitoclax-mediated apoptosis with distinct mechanistic

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana C. Henriques ◽  
Patrícia M. A. Silva ◽  
Bruno Sarmento ◽  
Hassan Bousbaa
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cell Fate ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Time Lapse ◽  
Antimitotic Drugs ◽  
Mitotic Slippage ◽  
Mitotic Death ◽  
Chronic Activation

AbstractAntimitotic drugs arrest cells in mitosis through chronic activation of the spindle assembly checkpoint (SAC), leading to cell death. However, drug-treated cancer cells can escape death by undergoing mitotic slippage, due to premature mitotic exit. Therefore, overcoming slippage issue is a promising chemotherapeutic strategy to improve the effectiveness of antimitotics. Here, we antagonized SAC silencing by knocking down the MAD2-binding protein p31comet, to delay mitotic slippage, and tracked cancer cells treated with the antimitotic drug paclitaxel, over 3 days live-cell time-lapse analysis. We found that in the absence of p31comet, the duration of mitotic block was increased in cells challenged with nanomolar concentrations of paclitaxel, leading to an additive effects in terms of cell death which was predominantly anticipated during the first mitosis. As accumulation of an apoptotic signal was suggested to prevent mitotic slippage, when we challenged p31comet-depleted mitotic-arrested cells with the apoptosis potentiator Navitoclax (previously called ABT-263), cell fate was shifted to accelerated post-mitotic death. We conclude that inhibition of SAC silencing is critical for enhancing the lethality of antimitotic drugs as well as that of therapeutic apoptosis-inducing small molecules, with distinct mechanisms. The study highlights the potential of p31comet as a target for antimitotic therapies.

scholarly journals Consequences of mitotic slippage for antimicrotubule drug therapy

2017 ◽  
Vol 24 (9) ◽  
pp. T97-T106 ◽  
Author(s):  
Bing Cheng ◽  
Karen Crasta
Keyword(s):  
Cell Death ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Cell ◽  
G1 Arrest ◽  
Front Line ◽  
Cell Fates ◽  
Mitotic Slippage ◽  
Drug Treatment Outcomes ◽  
Antimicrotubule Agents ◽  
Sustained Activation

Antimicrotubule agents are commonly utilised as front-line therapies against several malignancies, either by themselves or as combination therapies. Cell-based studies have pinpointed the anti-proliferative basis of action to be a consequence of perturbation of microtubule dynamics leading to sustained activation of the spindle assembly checkpoint, prolonged mitotic arrest and mitotic cell death. However, depending on the biological context and cell type, cells may take an alternative route besides mitotic cell death via a process known as mitotic slippage. Here, mitotically arrested cells ‘slip’ to the next interphase without undergoing proper chromosome segregation and cytokinesis. These post-slippage cells in turn have two main cell fates, either cell death or a G1 arrest ensuing in senescence. In this review, we take a look at the factors determining mitotic cell death vs mitotic slippage, post-slippage cell fates and accompanying features, and their consequences for antimicrotubule drug treatment outcomes.

scholarly journals APCFZR1 prevents nondisjunction in mouse oocytes by controlling meiotic spindle assembly timing

2012 ◽  
Vol 23 (20) ◽  
pp. 3970-3981 ◽  
Author(s):  
Janet E. Holt ◽  
Simon I. R. Lane ◽  
Phoebe Jennings ◽  
Irene García-Higuera ◽  
Sergio Moreno ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Cell ◽  
Meiotic Spindle ◽  
Genome Integrity ◽  
Mitotic Cell Cycle ◽  
Anaphase Promoting Complex ◽  
Mouse Oocytes ◽  
M Phase ◽  
Chromosome Nondisjunction

FZR1 is an anaphase-promoting complex (APC) activator best known for its role in the mitotic cell cycle at M-phase exit, in G1, and in maintaining genome integrity. Previous studies also established that it prevents meiotic resumption, equivalent to the G2/M transition. Here we report that mouse oocytes lacking FZR1 undergo passage through meiosis I that is accelerated by ∼1 h, and this is due to an earlier onset of spindle assembly checkpoint (SAC) satisfaction and APCCDC20 activity. However, loss of FZR1 did not compromise SAC functionality; instead, earlier SAC satisfaction was achieved because the bipolar meiotic spindle was assembled more quickly in the absence of FZR1. This novel regulation of spindle assembly by FZR1 led to premature bivalent attachment to microtubules and loss of kinetochore-bound MAD2. Bivalents, however, were observed to congress poorly, leading to nondisjunction rates of 25%. We conclude that in mouse oocytes FZR1 controls the timing of assembly of the bipolar spindle and in so doing the timing of SAC satisfaction and APCCDC20 activity. This study implicates FZR1 as a major regulator of prometaphase whose activity helps to prevent chromosome nondisjunction.

scholarly journals Unliganded progesterone receptors attenuate taxane-induced breast cancer cell death by modulating the spindle assembly checkpoint

2011 ◽  
Vol 131 (1) ◽  
pp. 75-87 ◽  
Author(s):  
Melanie M. Badtke ◽  
Purevsuren Jambal ◽  
Wendy W. Dye ◽  
Monique A. Spillman ◽  
Miriam D. Post ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Spindle Assembly Checkpoint ◽  
Progesterone Receptors ◽  
Spindle Assembly ◽  
Cancer Cell Death

Adapt or die: how eukaryotic cells respond to prolonged activation of the spindle assembly checkpoint

2010 ◽  
Vol 38 (6) ◽  
pp. 1645-1649 ◽  
Author(s):  
Valentina Rossio ◽  
Elena Galati ◽  
Simonetta Piatti
Keyword(s):  
Cell Death ◽  
Error Correction ◽  
Mitotic Spindle ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Model System ◽  
Eukaryotic Cells ◽  
Variable Amount ◽  
Mitotic Slippage ◽  
Surveillance Mechanism

Many cancer-treating compounds used in chemotherapies, the so-called antimitotics, target the mitotic spindle. Spindle defects in turn trigger activation of the SAC (spindle assembly checkpoint), a surveillance mechanism that transiently arrests cells in mitosis to provide the time for error correction. When the SAC is satisfied, it is silenced. However, after a variable amount of time, cells escape from the mitotic arrest, even if the SAC is not satisfied, through a process called adaptation or mitotic slippage. Adaptation weakens the killing properties of antimitotics, ultimately giving rise to resistant cancer cells. We summarize here the mechanisms underlying this process and propose a strategy to identify the factors involved using budding yeast as a model system. Inhibition of factors involved in SAC adaptation could have important therapeutic applications by potentiating the ability of antimitotics to cause cell death.

scholarly journals Inhibition of clathrin by pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells

2013 ◽  
Vol 12 (1) ◽  
pp. 4 ◽  
Author(s):  
Charlotte M Smith ◽  
Volker Haucke ◽  
Adam McCluskey ◽  
Phillip J Robinson ◽  
Megan Chircop
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly

scholarly journals Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Haruna Ebisu ◽  
Kana Shintani ◽  
Takumi Chinen ◽  
Yoko Nagumo ◽  
Shuya Shioda ◽  
...  
Keyword(s):  
Cell Death ◽  
Side Effects ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Combined Treatment ◽  
Specific Inhibitor ◽  
Mitotic Cell ◽  
Tubulin Inhibitor ◽  
Tubulin Inhibitors ◽  
Bi 2536

α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor. The cytotoxicity of gatastatin was relatively weak compared with that of the conventional MT inhibitors, paclitaxel and vinblastine. To improve the cytotoxicity, we screened the chemicals that improve the effects of gatastatin and found that BI 2536, a Plk1 inhibitor, greatly increases the cytotoxicity of gatastatin. Co-treatment with gatastatin and BI 2536 arrested cell cycle progression at mitosis with abnormal spindles. Moreover, mitotic cell death induced by the combined treatment was suppressed by the Mps1 inhibitor, reversine. These findings suggest that co-treatment with Plk1 and γ-tubulin inhibitors causes spindle assembly checkpoint-dependent mitotic cell death by impairing centrosome functions. These results raise the possibility of Plk1 and γ-tubulin inhibitor co-treatment as a novel cancer chemotherapy.

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