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. 2018 Mar;19(3):e45440.
doi: 10.15252/embr.201745440. Epub 2018 Feb 19.

Perturbing Mitosis for Anti-Cancer Therapy: Is Cell Death the Only Answer?

Free PMC article

Perturbing Mitosis for Anti-Cancer Therapy: Is Cell Death the Only Answer?

Manuel Haschka et al. EMBO Rep. .
Free PMC article


Interfering with mitosis for cancer treatment is an old concept that has proven highly successful in the clinics. Microtubule poisons are used to treat patients with different types of blood or solid cancer since more than 20 years, but how these drugs achieve clinical response is still unclear. Arresting cells in mitosis can promote their demise, at least in a petri dish. Yet, at the molecular level, this type of cell death is poorly defined and cancer cells often find ways to escape. The signaling pathways activated can lead to mitotic slippage, cell death, or senescence. Therefore, any attempt to unravel the mechanistic action of microtubule poisons will have to investigate aspects of cell cycle control, cell death initiation in mitosis and after slippage, at single-cell resolution. Here, we discuss possible mechanisms and signaling pathways controlling cell death in mitosis or after escape from mitotic arrest, as well as secondary consequences of mitotic errors, particularly sterile inflammation, and finally address the question how clinical efficacy of anti-mitotic drugs may come about and could be improved.

Keywords: BCL2 family; apoptosis; mitotic arrest; p53; slippage.


Figure 1
Figure 1. Anti‐mitotic drugs activate the spindle assembly checkpoint (SAC)
Unattached kinetochores trigger the activation of the SAC, leading to inhibition of prometaphase to anaphase transition and mitosis by blocking the activity of the APC/C E3 ligase complex. The mitotic checkpoint complex (MCC) thereby inhibits CDC20 from aiding substrate recognition by the APC/C (e.g., cyclin B or securin, degraded for mitotic exit), thereby enhancing mitotic arrest. MCC function can be antagonized by p31comet that can drive mitotic exit but seemingly also exerts alternative anti‐apoptotic functions in cells arrested in mitosis.
Figure 2
Figure 2. Multiple independent pathways can lead to p53 stabilization
In steady state, cytoplasmic p53 levels are kept low by continuous MDM2‐mediated ubiquitination and proteasomal degradation. Within the canonical DNA damage response, p53/MDM2 interactions are neutralized by phosphorylation of p53, abrogating MDM2 binding, that are executed by DDR kinases ATM, ATR, CHK2, and CHK1, depending on the type of DNA damage encountered. Cells spending an extended period of time in mitosis are also able to activate p53 for subsequent cell cycle arrest in the next G1‐phase. There, MDM2 activity is antagonized by the activity of a de‐ubiquitinating enzyme, USP28, all held together by the p53‐binding protein 53BP1. Finally, upon cytokinesis failure, extra centrosomes present in such cells activate the PIDDosome multiprotein complex, comprised out of the p53‐induced protein with a death domain (PIDD)1, a linker protein called RAIDD and a protease of the caspase family, that is, caspase‐2. Upon activation in the PIDDosome, caspase‐2 can process MDM2, removes its E3 ligase domain, and thereby promotes p53 stabilization.
Figure 3
Figure 3. BCL2 family proteins implicated in the control of mitotic cell death or cell death after mitotic slippage
(A) In healthy cells, a homeostatic equilibrium between cell death initiating BH3‐only proteins (blue), anti‐apoptotic BCL2 family proteins (green), and cell death executioners (pink/purple) is maintained. (B) Upon perturbation of this equilibrium, for example, by the action of anti‐mitotic drugs and prolonged arrest in mitosis, a series of events, including phosphorylation on and proteasomal degradation of pro‐survival BCL2 proteins, shifts the balance, favoring BAX/BAK1 activation. (C) Mitotic slippage or SAC adaptation can allow escape form mitotic cell death, yet newly initiated or carried over signaling cues impact on cell fate of such “post‐mitotic” cells. This can culminate in the induction of cell death, again potentially involving p53 plus a set of BCL2 family proteins that may have become active or changed in quantity in the preceding and prolonged M‐phase.
Figure 4
Figure 4. BCL2 family proteins targeted by phosphorylation in mitosis
The BCL2 protein family controls cell death upon extended mitotic arrest. Multiple phosphorylation events of pro‐ and anti‐apoptotic family members have been found in mitosis. Not all of them have been functionally characterized, but generally, it is believed that phosphorylation on pro‐survival proteins reduces their function, while the same type of modification promotes the death function of pro‐apoptotic BH3‐only proteins. A detailed list of reported phosphorylation events in and out of mitosis, their potential impact on function, the kinases and phosphatases involved, and the related reference can be extracted from Table 1.
Figure 5
Figure 5. Linking mitotic arrest and slippage to inflammation and immunity
(A) The dsDNA immune sensor cGAS, found associated with chromatin in mitosis, can synthesize a second messenger cyclic AMP/GMP from ATP and GTP that activates an ER‐resident signaling molecule, stimulator of interferon genes (STING). STING can trigger the activation of transcription factors, including the interferon response factor (IRF)3 and NF‐κB, leading to the production type I interferons, IFN, as well as a set of inflammatory cytokines and chemokines to alert the immune system and neighboring cells. A non‐transcriptional cell death activating function of IRF3 at mitochondria may contribute to mitotic cell death directly. Moreover, mitochondrial outer membrane permeabilization in a minority of mitochondria (miMOMP), frequently seen during mitotic arrest, could lead to NF‐κB‐driven inflammation when caspase activation is impaired while released mitochondrial (mt)DNA could lead to STING‐dependent IFN production. (B) Errors in mitosis that lead to micronucleation in the next G1‐phase, such as chromosome missegregation or slippage, alert the immune system via recruiting the cGAS/STING signaling pathway, described above. cGAS enters micronuclei upon lamin breakdown, binds to nucleosomal chromatin, and produces the second messenger cGAMP for STING activation and IFN signaling. Cytokinesis failure that does not lead to micronucleation, yet tetraploidy, may engage pro‐inflammatory signaling via the activation of the so‐called NEMO–PIDDosome complex, leading to NF‐κB activation.

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