Targeting Mitotic Exit Leads to Tumor Regression In Vivo: Modulation by Cdk1, Mastl, and the PP2A/B55α,δ Phosphatase

Abstract

Targeting mitotic exit has been recently proposed as a relevant therapeutic approach against cancer. By using genetically engineered mice, we show that the APC/C cofactor Cdc20 is essential for anaphase onset in vivo in embryonic or adult cells, including progenitor/stem cells. Ablation of Cdc20 results in efficient regression of aggressive tumors, whereas current mitotic drugs display limited effects. Yet, Cdc20 null cells can exit from mitosis upon inactivation of Cdk1 and the kinase Mastl (Greatwall). This mitotic exit depends on the activity of PP2A phosphatase complexes containing B55α or B55δ regulatory subunits. These data illustrate the relevance of critical players of mitotic exit in mammals and their implications in the balance between cell death and mitotic exit in tumor cells.

Killing cells by targeting mitosis

“…We have recently demonstrated that impairing cyclin B1 degradation in vivo by genetic elimination of Cdc20 is much more efficient in killing tumor cells than targeting the spindle assembly with classical poisons or new drugs inhibiting Eg5 or Plk1. 70 These observations are in agreement with the pioneer results using RNA interference (RNAi) against Cdc20 or expressing a non-degradable mutant of cyclin B1 in several tumor cell lines. 71 Whereas classical antimitotic drugs (vincristine or taxol) and new available mitotic inhibitors against Plk1 or kinesin Eg5 (BI2536 or monastrol, respectively) only induce a partial response in aggressive tumors, Cdc20 ablation results in complete metaphase arrest, leading to massive apoptotic cell death and complete tumor elimination in vivo.…”

“…71 Whereas classical antimitotic drugs (vincristine or taxol) and new available mitotic inhibitors against Plk1 or kinesin Eg5 (BI2536 or monastrol, respectively) only induce a partial response in aggressive tumors, Cdc20 ablation results in complete metaphase arrest, leading to massive apoptotic cell death and complete tumor elimination in vivo. 70 Importantly, mitotic exit inhibition also affects pRb-null, p53-null or SAC-deficient cells, 70,71 suggesting widespread uses. In vitro, Cdc20-null tumor cells cannot escape from the metaphase arrest and die of mitotic cell death in 6-30 h. 70 Altogether, these results suggest that drugs that target Cdc20 or other components involved in cyclin B1 degradation, such as core components of the APC/C or the proteasome, could be quite effective in killing tumor cells.…”

“…70 Importantly, mitotic exit inhibition also affects pRb-null, p53-null or SAC-deficient cells, 70,71 suggesting widespread uses. In vitro, Cdc20-null tumor cells cannot escape from the metaphase arrest and die of mitotic cell death in 6-30 h. 70 Altogether, these results suggest that drugs that target Cdc20 or other components involved in cyclin B1 degradation, such as core components of the APC/C or the proteasome, could be quite effective in killing tumor cells. Indeed, a genome-wide RNAi screen has recently identified synthetic lethal interaction between K-RAS oncogenic signaling and the inhibition of core subunits of the APC/C, such as APC1 and APC4 72 .…”

“…Consequently, a proapoptotic signal independent of the SAC accumulates to trigger apoptosis during mitotic arrest. 70,71 Recent data suggest that caspases are not required for the activity of the mitotic checkpoint or for mitotic slippage, 77 suggesting that mitotic and death pathways are two independent processes. How these two processes talk to each other and how cell death is triggered and modulated during prolonged mitosis is a central question that needs to be answered.…”

“…Cdk1 and Mastl inhibition strongly synergizes to promote exit from mitosis and tumor cell survival in vitro. 70 Thus, whereas APC/C inhibition may enhance the therapeutic benefits of specific mitotic drugs, inhibition of Cdk1 or Mastl should be avoided. In summary, targeting mitotic exit offers effective possibilities for killing tumor cells, and further investigation will be required to identify druggable targets and to validate this therapeutic strategy in specific tumors in vivo.…”