Mitotic Catastrophe Review

Mitotic Catastrophe Review

This blog focusses on the underlying mechanisms and consequences of this intriguing phenomenon, which occurs during aberrant cell division. Our comprehensive analysis provides a scientific examination of Mitotic Catastrophe, including its relevance in cancer research and potential therapeutic applications. Stay informed with the latest advancements and discoveries in this field as we explore the scientific intricacies of Mitotic Catastrophe in this informative review

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Hallmarks of mitotic catastrophe

The hallmarks of mitotic catastrophe, initially observed by Spear and Glucksmann in their pioneering studies during the 1930s and 1940s, shed light on the cellular response to radiation treatment. In their experiments, exponentially-growing cells were exposed to radiation, leading to intriguing observations. It was discovered that these cells experienced cell death precisely at the first mitotic transition following radiation exposure. Remarkably, the affected cells displayed profound numerical and structural karyotypic abnormalities, further emphasizing the disruptive consequences of mitotic catastrophe.

These groundbreaking findings not only established the existence of mitotic catastrophe as a distinct phenomenon but also underscored its association with genetic instability. The observed karyotypic abnormalities served as tangible evidence of the intricate damage inflicted upon the genome during this catastrophic event. Understanding the repercussions of mitotic catastrophe has since become crucial in various fields, ranging from cancer research to therapeutic interventions aimed at targeting aberrant cell proliferation.

By recognizing the historical significance of Spear and Glucksmann's work, we can appreciate the foundational knowledge that has propelled our understanding of mitotic catastrophe and its implications in cellular biology and pathology.

The potential causes and consequences of a mitotic catastrophe.

Mitotic failure

Elaborating on the description of mitotic catastrophe, the Kroemer group has provided a comprehensive understanding of this phenomenon as a cellular mechanism that actively senses and responds to mitotic failure. When cells encounter errors or abnormalities during mitosis, mitotic catastrophe serves as a regulatory mechanism, directing the cell toward an irreversible fate. This fate can manifest as apoptosis, necrosis, or senescence, depending on the specific circumstances and cellular context.

By driving cells with mitotic abnormalities towards these antiproliferative fates, mitotic catastrophe can be viewed as an oncosuppressive mechanism. Its primary role is to divert potentially aneuploid cells, which possess an abnormal number of chromosomes, away from continued proliferation. This crucial redirection helps prevent the propagation of genetically unstable and potentially harmful cells within the body.

The concept of mitotic catastrophe as an oncosuppressive mechanism highlights its significance in maintaining genomic stability and preventing the development of cancerous cells. It represents an inherent safeguarding process that acts as a barrier against the uncontrolled growth and division of cells harboring significant genetic anomalies.

Mitotic failure

Mitotic slippage

Firstly, cells may experience death without exiting mitosis (mitotic death), which can occur due to severe chromosomal abnormalities or spindle assembly defects. This type of cell death can result in the release of fragmented DNA and other cellular debris, triggering an inflammatory response in the surrounding tissue. Understanding the mechanisms underlying mitotic death can help identify potential targets for novel anti-cancer therapies.

Secondly, cells may progress through aberrant mitosis into a subsequent G1 phase (mitotic slippage), where they undergo either immediate or delayed cell death. Mitotic slippage allows cells with uncorrected DNA damage or spindle defects to escape mitotic arrest and enter the next cell cycle phase. However, these cells often accumulate genomic instability and can eventually undergo apoptotic or non-apoptotic cell death, highlighting the importance of targeting mitotic slippage as a potential therapeutic strategy.

Finally, cells may exit mitosis and become senescent, entering a state of irreversible cell cycle arrest. Senescent cells have been implicated in aging and various age-related diseases, as they exhibit altered gene expression patterns and can secrete pro-inflammatory molecules, collectively known as the senescence-associated secretory phenotype (SASP). Developing interventions that selectively eliminate or modulate senescent cells holds promise for mitigating age-related pathologies and promoting healthy aging.

Proteolysis of cyclin B during mitotic catastrophe

Mitotic slippage, a phenomenon that can occur in the absence of SAC satisfaction, allows cells to bypass the inactivation of APC through alternative proteolysis of its substrate, cyclin B1. This proteolysis of cyclin B results in the premature inactivation of Cdk1, the mitotic kinase, leading to mitotic slippage and the direct progression of tetraploid cells into a subsequent G1 phase. However, it is important to note that mitotic catastrophe is primarily induced by perturbations of the SAC. For instance, MTAs (microtubule-targeting agents) directly bind to tubulin, disrupting spindle formation and promoting mitotic catastrophe. Moreover, the depletion of the SAC checkpoint protein Chk1, a kinase that regulates mitotic entry, can drive cells towards mitotic catastrophe by triggering the premature activation of Cdk1. This additional information further highlights the intricate mechanisms involved in mitotic catastrophe and the various factors that can contribute to its occurrence.

Duration of mitotic arrest

Reports have indicated that cell commitment to mitotic catastrophe is highly dependent on the duration of mitotic arrest. A report from the Taylor group determined that 15 hr was the cutoff point for the treatment of HeLa cells with MTAs, beyond which cell commitment to mitotic catastrophe was irreversible. It has been proposed that this duration effect is directly due to the prolonged activation of Cdk1. This sustained activation of Cdk1 leads to the sustained phosphorylation of its downstream targets, such as Bcl-2 family members and other cell cycle regulators, ultimately driving the cell toward mitotic catastrophe. Moreover, recent studies have suggested that the duration of mitotic arrest can also influence the DNA damage response pathway, leading to additional cellular responses, including apoptosis and senescence. Further investigations are needed to elucidate the precise molecular mechanisms underlying the relationship between the duration of mitotic arrest and the commitment to mitotic catastrophe.

Pro-longed mitotic arrest (D-mitosis)

Cdk1 is the main kinase active during both typical mitosis and prolonged mitotic arrest, which has been termed D-mitosis and it is thought that the Cdk1-dependent hyperphosphorylation of Bcl-2/Bcl-XL during prolonged mitotic arrest acts as a molecular switch from anti-apoptotic to pro-apoptotic Cdk1 signaling. This switch triggers a cascade of events that promote cell death. Furthermore, the Cdk1-dependent phosphorylation of the anti-apoptotic Bcl-2 member Mcl1 leads to its degradation during prolonged mitotic arrest. Contemporaneous work from several groups indicates that Mcl1 degradation is carried out by either the APC/C (Anaphase-Promoting Complex/Cyclosome) or the related ubiquitination complex SCF (Skp1-Cullin-F-box protein), via their respective adaptor proteins Cdc20 and Fbw7. These E3 ligases recognize specific motifs on Mcl1 and target it for ubiquitination and subsequent proteasomal degradation. The degradation of Mcl1 further sensitizes the cell to undergo apoptosis during prolonged mitotic arrest, contributing to the irreversible commitment to mitotic catastrophe.

Ubiquitination during mitotic catastrophe

It is currently unclear whether these results are contradictory or represent an example of a cooperative mechanism between the two ubiquitin ligase complexes, which has previously been described. Previous studies have shown that the APC/C and SCF complexes can function cooperatively, targeting different substrates for ubiquitination and degradation during specific cellular processes. Therefore, it is plausible that both complexes, APC/C and SCF, may contribute to Mcl1 degradation during prolonged mitotic arrest, acting in a coordinated manner to ensure efficient cell death induction. Additionally, given that Cdk1 is such a prolific kinase during mitosis, it is likely that Cdk1-dependent phosphorylation of numerous substrates plays a crucial role in the induction of cell death due to prolonged mitotic arrest. These phosphorylation events may trigger a cascade of signaling events that collectively contribute to the irreversible commitment to mitotic catastrophe.

Oncosuppressive mechanism

The Nomenclature Committee on Cell Death (NCCD) provides unified criteria for the definition of cell death modalities through morphological and biochemical hallmarks. According to the current recommendations of the NCCD published in 2011, mitotic catastrophe would not constitute a pure cell death executioner pathway, but rather an oncosuppressive mechanism that serves multiple functions. Firstly, it is initiated by perturbation of the mitotic machinery, which can result from various cellular stresses or defects in mitotic checkpoints. Secondly, it occurs during mitosis, specifically when cells are undergoing nuclear division. Thirdly, it is concomitant with mitotic arrest, where cells are unable to proceed through mitosis due to various reasons such as DNA damage or abnormal spindle formation. Finally, the outcome of mitotic catastrophe can vary, leading to either cell death or senescence, depending on the cellular context and the extent of damage incurred during mitotic arrest. This indicates that mitotic catastrophe acts as a safeguard mechanism to prevent the propagation of damaged cells and promote tumor suppression.

Caspase activation during mitotic catastrophe

Caspase activation has been known to be involved in mitotic cell death, playing distinct roles in different scenarios. Particularly, the involvement of caspase-2 has been observed during mitotic catastrophe, while caspases-3 and -8 have been implicated in MTA-induced apoptosis. Caspase-2 activation during mitotic catastrophe has been linked to the induction of apoptotic cell death. It has been proposed that caspase-2 activation during mitosis acts as a checkpoint to eliminate cells with severe DNA damage or aberrant mitotic progression. In contrast, the activation of caspases-3 and -8 during MTA-induced apoptosis contributes to the execution of cell death through the cleavage of downstream targets.

Interestingly, the phosphorylation of caspase-2 and caspase-9 during mitosis has been shown to have a cytoprotective effect against the initiation of apoptosis. Phosphorylation of these caspases during mitosis can prevent their activation and subsequent apoptotic signaling. This phosphorylation event serves as a mechanism to protect cells from undergoing premature apoptosis during normal mitotic processes. However, the precise regulatory mechanisms and signaling pathways involved in the phosphorylation of caspase-2 and caspase-9 during mitosis are still being investigated.

Apoptogenic factors

The activation of caspases during mitotic cell death is often accompanied by the release of mitochondrial apoptogenic factors, such as cytochrome C, DNAses AIF1, and endonuclease G. This indicates that in these instances, mitotic cell death occurs through a classical apoptotic mechanism. The release of these mitochondrial apoptogens triggers a cascade of events leading to caspase activation and subsequent apoptotic cell death.

However, recent studies have challenged the notion that caspase activation is an absolute requirement for the initiation of programmed cell death during mitosis. These studies have revealed that the release of mitochondrial apoptogens can induce cell death even in the absence of caspase activation. This suggests the existence of alternative cell death pathways or mechanisms operating during mitotic cell death. These caspase-independent pathways may involve other proteases or cellular factors that can execute cell death programs in response to mitotic perturbations. The precise molecular mechanisms underlying these caspase-independent cell death pathways during mitosis are still being actively investigated.

Caspase independent mitotic death

This newly identified pathway, termed caspase-independent mitotic death (CIMD), represents an alternative mechanism of cell death during mitosis. The initiation of CIMD involves the activation of spindle checkpoint proteins, with the participation of both Bub1/Bub3 and the mitotic kinase Plk1. These proteins play integral roles in ensuring proper mitotic progression and chromosome segregation. Activation of the spindle checkpoint proteins triggers signaling cascades that ultimately lead to CIMD.

However, there have been contradictory reports regarding the regulatory factors involved in CIMD. Some studies suggest that CIMD is a p53-dependent process, with p53 playing a crucial role in orchestrating cell death during mitosis. In contrast, other reports propose that CIMD may operate through the involvement of the p53 homolog, p73, in the absence of functional p53. The exact regulatory mechanisms and the contribution of p53 or p73 in CIMD remain areas of ongoing research.

Targeting mitotic catastrophe

The characterization of the pathways involved in mitotic catastrophe is currently a subject of intense experimental effort, driven by the potential therapeutic benefits that this avenue of research offers. Many current chemotherapeutic agents, such as doxorubicin, are utilized at concentrations that non-selectively induce apoptosis at any stage of the cell cycle. However, there is emerging evidence suggesting that these chemotherapeutics could be more effectively implemented at lower concentrations, specifically targeting and selectively inducing mitotic catastrophe. This approach could potentially reduce off-target effects associated with high doses of chemotherapy and enhance the efficacy of treatment.

The inherent karyotypic abnormalities commonly found in most tumor cells make them particularly vulnerable to cell death induced by mitotic catastrophe. Tumors often display genomic instability, which leads to aberrant mitotic processes and compromised cell cycle checkpoints. Consequently, the introduction of additional stressors, such as mitotic stress, can push these already compromised cells beyond their viability limits, resulting in cell death. Exploiting the vulnerability of tumor cells to mitotic catastrophe could provide a more targeted and efficient approach for cancer treatment.

Mitotic Castastrophe Markers

Cell death strategies

Several novel strategies for inducing mitotic catastrophe are currently under investigation in the field of cancer research. One promising approach involves targeting the kinesin spindle protein (KSP), which plays a crucial role in ensuring the correct bipolar spindle orientation during mitosis. Inhibition of this motor protein disrupts the proper spindle formation and leads to mitotic catastrophe characterized by monoastral mitoses, where cells possess only a single aster instead of a bipolar spindle.

The KSP inhibitor monastrol, derived from the term "monoastral," specifically targets and inhibits the activity of KSP. By blocking KSP function, monastrol induces mitotic catastrophe in cancer cells, preventing proper chromosome alignment and segregation during mitosis. This disruption of mitotic processes ultimately leads to cell death.

Targeting KSP and other key regulators of mitotic processes represents a promising avenue for developing novel anti-cancer therapies. By selectively disrupting mitotic spindle dynamics and inducing mitotic catastrophe, these strategies aim to preferentially kill cancer cells while sparing normal cells.

Mitotic spindle formation

The chromosomal passenger complex (CPC) is a multiprotein complex required for microtubule stabilization and mitotic spindle formation. As such, specific small-molecule chemical inhibition of components of this complex presents an attractive target for the induction of mitotic catastrophe. Aurora B kinase is an enzymatic component of the CPC, and Aurora B kinase inhibitors including AZD1152 and VX-680 are currently in clinical trials as putative therapies for various hematopoietic malignancies. Survivin is a structural component of the CPC, and has been investigated as a therapeutic target. However, so far the only survivin inhibitor to reach Phase II clinical trial, YM155, has failed to demonstrate therapeutic efficacy.

Degradation of Mcl-1 during apoptosis

It has been proposed that cell death initiation following prolonged mitotic arrest may be due the degradation of Mcl-1, allowing for the release of the proapoptotic BH3-only proteins, Bim and Noxa, and subsequent apoptosome formation due to the slow net dephosphorylation of caspase-9, which may lead to the activation of cell death. However, exactly how upstream activation of cell death occurs following prolonged mitotic arrest resulting in mitotic catastrophe remains unresolved.

In conclusion, the study of mitotic catastrophe offers valuable insights into the complex mechanisms underlying cell death during mitosis. Mitotic catastrophe represents a cellular response to perturbations in the mitotic machinery and can lead to either cell death or senescence. It involves diverse molecular events, including prolonged activation of Cdk1, release of mitochondrial apoptotic factors, and potential involvement of caspase-dependent or caspase-independent pathways. The characterization of these pathways and the identification of key regulatory factors are subjects of ongoing research efforts.

Written by Pragna Krishnapur

Pragna Krishnapur completed her bachelor degree in Biotechnology Engineering in Visvesvaraya Technological University before completing her masters in Biotechnology at University College Dublin.

11th Jul 2023 Pragna Krishnapur, MSc

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