PKCε Controls Mitotic Progression by Regulating Centrosome Migration and Mitotic Spindle Assembly

To form a proper mitotic spindle, centrosomes must be duplicated and driven poleward in a timely and controlled fashion. Improper timing of centrosome separation and errors in mitotic spindle assembly may lead to chromosome instability, a hallmark of cancer. Protein kinase C epsilon (PKCε) has recently emerged as a regulator of several cell-cycle processes associated with the resolution of mitotic catenation during the metaphase-anaphase transition and in regulating the abscission checkpoint. However, an engagement of PKCε in earlier (pre)mitotic events has not been addressed. Here, we now establish that PKCε controls prophase-to-metaphase progression by coordinating centrosome migration and mitotic spindle assembly in transformed cells. This control is exerted through cytoplasmic dynein function. Importantly, it is also demonstrated that the PKCε dependency of mitotic spindle organization is correlated with the nonfunctionality of the TOPO2A-dependent G₂ checkpoint, a characteristic of many transformed cells. Thus, PKCε appears to become specifically engaged in a programme of controls that are required to support cell-cycle progression in transformed cells, advocating for PKCε as a potential cancer therapeutic target.Implications: The close relationship between PKCε dependency for mitotic spindle organization and the nonfunctionality of the TOPO2A-dependent G₂ checkpoint, a hallmark of transformed cells, strongly suggests PKCε as a therapeutic target in cancer. Mol Cancer Res; 16(1); 3-15. ©2017 AACR.