Oncotarget

Research Papers:

ATP-competitive Plk1 inhibitors induce caspase 3-mediated Plk1 cleavage and activation in hematopoietic cell lines

Maeva Dufies, Damien Ambrosetti, Sonia Boulakirba, Anne Calleja, Coline Savy, Nathan Furstoss, Marwa Zerhouni, Julien Parola, Lazaro Aira-Diaz, Sandrine Marchetti, Francois Orange, Sandra Lacas-Gervais, Frederic Luciano, Arnaud Jacquel, Guillaume Robert, Gilles Pagès and Patrick Auberger _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2018; 9:10920-10933. https://doi.org/10.18632/oncotarget.23650

Metrics: PDF 1196 views  |   HTML 1987 views  |   ?  


Abstract

Maeva Dufies1,2, Damien Ambrosetti3, Sonia Boulakirba1,4, Anne Calleja1,4, Coline Savy1,4, Nathan Furstoss1, Marwa Zerhouni1, Julien Parola2, Lazaro Aira-Diaz1, Sandrine Marchetti1, Francois Orange5, Sandra Lacas-Gervais5, Frederic Luciano1,4, Arnaud Jacquel1,4, Guillaume Robert1,4, Gilles Pagès2 and Patrick Auberger1,4

1Université Côte d’Azur, C3M/Inserm U1065, Nice, France

2Université Côte d’Azur, Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR 7284, INSERM U 1081, Nice, France

3Université Côte d’Azur, CHU Nice, Department of Pathology, Nice, France

4Equipe Labellisée par la Fondation ARC (2017-2020), Paris, France

5Université Côte d’Azur, CCMA, Nice, France

Correspondence to:

Patrick Auberger, email: auberger@unice.fr

Keywords: Plk1; caspases; hematopoietic cells; G2M arrest; mitotic catastrophe

Received: December 11, 2017     Accepted: December 18, 2017     Published: December 23, 2017

ABSTRACT

Polo-like kinases (Plks) define a highly conserved family of Ser/Thr kinases with crucial roles in the regulation of cell division. Here we show that Plk1 is cleaved by caspase 3, but not by other caspases in different hematopoietic cell lines treated with competitive inhibitors of the ATP-binding pocket of Plk1. Intriguingly, Plk1 was not cleaved in cells treated with Rigosertib, a non-competitive inhibitor of Plk1, suggesting that binding of the inhibitor to the ATP binding pocket of Plk1 triggers a conformational change and unmasks a cryptic caspase 3 cleavage site on the protein. Cleavage occurs after Asp-404 in a DYSD/K sequence and separates the kinase domain from the two PBDs of Plk1. All Plk1 inhibitors triggered G2/M arrest, activation of caspases 2 and 3, polyploidy, multiple nuclei and mitotic catastrophe, albeit at higher concentrations in the case of Rigosertib. Upon BI-2536 treatment, Plk1 cleavage occurred only in the cytosolic fraction and cleaved Plk1 accumulated in this subcellular compartment. Importantly, the cleaved N-Terminal fragment of Plk1 exhibited a higher enzymatic activity than its non-cleaved counterpart and accumulated into the cytoplasm conversely to the full length and the C-Terminal Plk1 fragments that were found essentially into the nucleus. Finally, the DYSD/K cleavage site was highly conserved during evolution from c. elegans to human. In conclusion, we described herein for the first time a specific cleavage of Plk1 by caspase 3 following treatment of cancer cells with ATP-competitive inhibitors of Plk1.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 23650