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.

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 Inhibition of Bcl-xL sensitizes cells to mitotic blockers, but not mitotic drivers

Open Biology ◽  
2016 ◽  
Vol 6 (8) ◽  
pp. 160134 ◽  
Author(s):  
Ailsa Bennett ◽  
Olivia Sloss ◽  
Caroline Topham ◽  
Louisa Nelson ◽  
Anthony Tighe ◽  
...  
Keyword(s):  
Cell Fate ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Time Lapse ◽  
Intrinsic Apoptosis ◽  
Pharmacological Agents ◽  
Apoptosis Pathway ◽  
Combination Treatments ◽  
Intrinsic Apoptosis Pathway ◽  
Coupling Time

Cell fate in response to an aberrant mitosis is governed by two competing networks: the spindle assembly checkpoint (SAC) and the intrinsic apoptosis pathway. The mechanistic interplay between these two networks is obscured by functional redundancy and the ability of cells to die either in mitosis or in the subsequent interphase. By coupling time-lapse microscopy with selective pharmacological agents, we systematically probe pro-survival Bcl-xL in response to various mitotic perturbations. Concentration matrices show that BH3-mimetic-mediated inhibition of Bcl-xL synergises with perturbations that induce an SAC-mediated mitotic block, including drugs that dampen microtubule dynamics, and inhibitors targeting kinesins and kinases required for spindle assembly. By contrast, Bcl-xL inhibition does not synergize with drugs which drive cells through an aberrant mitosis by overriding the SAC. This differential effect, which is explained by compensatory Mcl-1 function, provides opportunities for patient stratification and combination treatments in the context of cancer chemotherapy.

scholarly journals Inhibitor of the spindle assembly checkpoint surpasses apoptosis sensitizer in synergy with taxanes

2018 ◽  
Author(s):  
Teng-Long Han ◽  
Zhi-Xin Jiang ◽  
Yun-Tian Li ◽  
Deng-Shan Wu ◽  
Jun Ji ◽  
...  
Keyword(s):  
Cell Death ◽  
Treatment Response ◽  
Tumor Cells ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Slippage ◽  
Induced Apoptosis

AbstractThe antitumor effect of taxanes have been attributed to their ability to induce mitotic arrest through activation of the spindle assembly checkpoint. Cell death following prolonged mitotic arrest is mediated by the intrinsic apoptosis pathway. Thus, apoptosis sensitizers which inhibit antiapoptotic Bcl-2 family proteins has been shown to enhance taxanes-induced cell death. By contrast, spindle checkpoint disruption facilitates mitotic slippage and is thought to promote taxanes resistance. Notably, other modes of cell death also contribute to treatment outcomes. Here we show that inhibition of the spindle checkpoint suppresses taxanes induced apoptosis but increases terminal growth arrest of tumor cells with features of cellular senescence. By using clonogenic assay which measures the net result of multiple forms of cell death and is more reflective of therapeutic response, our finding suggests apoptosis is not a major determinant of antitumor efficacy of taxanes, whereas spindle checkpoint inhibitor displays a long-term advantage over apoptosis sensitizer in blocking colony outgrowth of tumor cells when combined with different microtubule toxins, therefore represents a superior therapeutic strategy.SIGNIFICANCEApoptosis has long been regarded as the primary mechanism of anti-cancer efficacy of taxanes, while the role of the spindle assembly checkpoint (SAC) in treatment response to taxanes has been controversial. Either apoptosis sensitizer or inhibitor of SAC has been reported to synergize with taxanes. While inhibitor of antiapoptotic proteins potentiates taxanes induced apoptosis, inhibitor of SAC suppresses apoptosis by facilitating mitotic slippage, that is why it is implicated in taxanes resistance. By demonstrating that apoptotic rates are not associate with long-term treatment response, not only do we find that inhibitor of SAC displays a long-term advantage over apoptosis sensitizer in combination with taxanes, but we also resolve the dispute around the role of SAC in cellular response to taxanes.

scholarly journals Evidence that polyploidy in esophageal adenocarcinoma originates from mitotic slippage caused by defective chromosome attachments

2021 ◽  
Author(s):  
Stacey J. Scott ◽  
Xiaodun Li ◽  
Sriganesh Jammula ◽  
Ginny Devonshire ◽  
Catherine Lindon ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Esophageal Adenocarcinoma ◽  
Cell Biology ◽  
Time Lapse ◽  
Rna Seq ◽  
Cancer Evolution ◽  
Mitotic Slippage ◽  
Quantitative Immunofluorescence ◽  
Cancer Types ◽  
Eac Cells

AbstractPolyploidy is present in many cancer types and is increasingly recognized as an important factor in promoting chromosomal instability, genome evolution, and heterogeneity in cancer cells. However, the mechanisms that trigger polyploidy in cancer cells are largely unknown. In this study, we investigated the origin of polyploidy in esophageal adenocarcinoma (EAC), a highly heterogenous cancer, using a combination of genomics and cell biology approaches in EAC cell lines, organoids, and tumors. We found the EAC cells and organoids present specific mitotic defects consistent with problems in the attachment of chromosomes to the microtubules of the mitotic spindle. Time-lapse analyses confirmed that EAC cells have problems in congressing and aligning their chromosomes, which can ultimately culminate in mitotic slippage and polyploidy. Furthermore, whole-genome sequencing, RNA-seq, and quantitative immunofluorescence analyses revealed alterations in the copy number, expression, and cellular distribution of several proteins known to be involved in the mechanics and regulation of chromosome dynamics during mitosis. Together, these results provide evidence that an imbalance in the amount of proteins implicated in the attachment of chromosomes to spindle microtubules is the molecular mechanism underlying mitotic slippage in EAC. Our findings that the likely origin of polyploidy in EAC is mitotic failure caused by problems in chromosomal attachments not only improves our understanding of cancer evolution and diversification, but may also aid in the classification and treatment of EAC and possibly other highly heterogeneous cancers.

scholarly journals Depletion of Survivin suppresses docetaxel-induced apoptosis in HeLa cells by facilitating mitotic slippage

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Teng-Long Han ◽  
Hang Sha ◽  
Jun Ji ◽  
Yun-Tian Li ◽  
Deng-Shan Wu ◽  
...  
Keyword(s):  
Hela Cells ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Clonogenic Survival ◽  
Mitotic Arrest ◽  
Apoptosis Pathway ◽  
Mitotic Slippage ◽  
Intrinsic Apoptosis Pathway ◽  
Apoptosis Protein ◽  
Induced Apoptosis

AbstractThe anticancer effects of taxanes are attributed to the induction of mitotic arrest through activation of the spindle assembly checkpoint. Cell death following extended mitotic arrest is mediated by the intrinsic apoptosis pathway. Accordingly, factors that influence the robustness of mitotic arrest or disrupt the apoptotic machinery confer drug resistance. Survivin is an inhibitor of apoptosis protein. Its overexpression is associated with chemoresistance, and its targeting leads to drug sensitization. However, Survivin also acts specifically in the spindle assembly checkpoint response to taxanes. Hence, the failure of Survivin-depleted cells to arrest in mitosis may lead to taxane resistance. Here we show that Survivin depletion protects HeLa cells against docetaxel-induced apoptosis by facilitating mitotic slippage. However, Survivin depletion does not promote clonogenic survival of tumor cells but increases the level of cellular senescence induced by docetaxel. Moreover, lentiviral overexpression of Survivin does not provide protection against docetaxel or cisplatin treatment, in contrast to the anti-apoptotic Bcl-xL or Bcl-2. Our findings suggest that targeting Survivin may influence the cell response to docetaxel by driving the cells through aberrant mitotic progression, rather than directly sensitizing cells to apoptosis.

scholarly journals NF-κB activation enhances cell death by antimitotic drugs in human prostate cancer cells

2010 ◽  
Vol 9 (1) ◽  
pp. 182 ◽  
Author(s):  
Ricardo Parrondo ◽  
Alicia Pozas ◽  
Teresita Reiner ◽  
Priyamvada Rai ◽  
Carlos Perez-Stable
Keyword(s):  
Prostate Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Antimitotic Drugs

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 Active elimination of intestinal cells drives oncogenic growth in organoids

2020 ◽  
Author(s):  
Ana Krotenberg Garcia ◽  
Arianna Fumagalli ◽  
Huy Quang Le ◽  
Owen J. Sansom ◽  
Jacco van Rheenen ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Death ◽  
Cancer Cells ◽  
Cell Fate ◽  
Crucial Role ◽  
Intestinal Cells ◽  
Dependent Manner ◽  
Wild Type ◽  
Cell Competition ◽  
Type Population

AbstractCompetitive cell-interactions play a crucial role in quality control during development and homeostasis. Here we show that cancer cells use such interactions to actively eliminate wild-type intestine cells in enteroid monolayers and organoids. This apoptosis-dependent process boosts proliferation of intestinal cancer cells. The remaining wild-type population activates markers of primitive epithelia and transits to a fetal-like state. Prevention of this cell fate transition avoids elimination of wild-type cells and, importantly, limits the proliferation of cancer cells. JNK signalling is activated in competing cells and is required for cell fate change and elimination of wild-type cells. Thus, cell competition drives growth of cancer cells by active out-competition of wild-type cells through forced cell death and cell fate change in a JNK dependent manner.

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