ATP-competitive Plk1 inhibitors induce caspase 3-mediated Plk1 cleavage and activation in hematopoietic cell lines
| Autor: | Damien Ambrosetti, Maeva Dufies, Arnaud Jacquel, François Orange, Anne Calleja, Sonia Boulakirba, Marwa Zerhouni, Sandrine Marchetti, Frederic Luciano, Coline Savy, Nathan Furstoss, Gilles Pagès, Julien Parola, Lazaro Aira-Diaz, Guillaume Robert, Sandra Lacas-Gervais, Patrick Auberger |
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| Přispěvatelé: | Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Hôpital Pasteur [Nice] (CHU), Fondation ARC pour la recherche sur le cancer, Centre Commun de Microscopie Appliquée (CCMA), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell division [SDV]Life Sciences [q-bio] Caspase 3 [SDV.CAN]Life Sciences [q-bio]/Cancer [SDV.BC]Life Sciences [q-bio]/Cellular Biology Cleavage (embryo) PLK1 03 medical and health sciences hematopoietic cells [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Mitotic catastrophe mitotic catastrophe Caspase biology Kinase Chemistry Cell biology 030104 developmental biology Oncology Protein kinase domain caspases Plk1 biology.protein G2M arrest Research Paper |
| Zdroj: | Oncotarget Oncotarget, Impact journals, 2018, 9 (13), ⟨10.18632/oncotarget.23650⟩ |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.23650⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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