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

SummaryTargeting 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (152 K)Download as PowerPoint slideHighlights► Cdc20 is essential for anaphase onset in normal or tumoral cells ► Cdc20 ablation results in complete tumor regression in vivo due to apoptotic death ► Cdc20 null cells can exit from mitosis after inhibition of Cdk1 and Mastl ► Mammalian mitotic exit depends on the activation of PP2A-B55 phosphatases