- The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1-amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1-amplified HGSOC cells that may influence clinical paclitaxel response. PLK1 is overexpressed in many types of cancer, which correlates with poor prognosis. Here, we identified a novel synthetic lethal interaction of the clinical PLK1 inhibitor BI6727 and the microtubule-targeting drug paclitaxel in HGSOC cell lines with CCNE1-amplification and elucidated the underlying molecular mechanisms of this synergism. BI6727 synergistically induces apoptosis together with paclitaxel in different cell lines including a patient-derived primary ovarian cancer culture. Moreover, the inhibition of PLK1 reduced the paclitaxel-induced neurotoxicity in a neurite outgrowth assay. Mechanistically, the combinatorial treatment with BI6727/paclitaxel triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of anti-apoptotic BCL-2 family proteins, followed by significant loss of the mitochondrial membrane potential and activation of caspase-dependent effector pathways. This conclusion is supported by data showing that BI6727/paclitaxel-co-treatment stabilizes FBW7, a component of SCF-type ubiquitin ligases that bind and regulate key modulators of cell division and growth including MCL-1 and Cyclin E. This identification of a novel synthetic lethality of PLK1 inhibitors and a microtubule-stabilizing drug has important implications for developing PLK1 inhibitor-based combination treatments in CCNE1-amplified HGSOC cells.
MetadatenVerfasserangaben: | Sabrina Noack, Monika RaabORCiD, Yves MatthessORCiDGND, Mourad SanhajiORCiDGND, Andrea KrämerORCiDGND, Balázs Győrffy, Lars Kaderali, Ahmed el- Balat, Sven BeckerORCiDGND, Klaus StrebhardtORCiD |
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URN: | urn:nbn:de:hebis:30:3-468254 |
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DOI: | https://doi.org/10.18632/oncotarget.25386 |
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ISSN: | 1949-2553 |
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Pubmed-Id: | https://pubmed.ncbi.nlm.nih.gov/29899826 |
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Titel des übergeordneten Werkes (Englisch): | OncoTarget |
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Verlag: | Impact Journals LLC |
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Verlagsort: | [s. l.] |
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Dokumentart: | Wissenschaftlicher Artikel |
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Sprache: | Englisch |
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Jahr der Fertigstellung: | 2018 |
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Datum der Erstveröffentlichung: | 25.05.2018 |
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Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Datum der Freischaltung: | 03.07.2018 |
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Freies Schlagwort / Tag: | cell cycle; ovarian cancer; paclitaxel; protein kinases; sensitization |
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Jahrgang: | 9 |
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Ausgabe / Heft: | 40 |
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Seitenzahl: | 18 |
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Erste Seite: | 25842 |
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Letzte Seite: | 25859 |
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Bemerkung: | All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License. |
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HeBIS-PPN: | 435733656 |
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Institute: | Biowissenschaften / Biowissenschaften |
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| Medizin / Medizin |
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DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Lizenz (Deutsch): | Creative Commons - Namensnennung 3.0 |
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