Tripolin A,a Novel Small-Molecule Inhibitor of Aurora A Kinase,Reveals New Regulation of HURP's Distribution on Microtubules |
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Authors: | Iliana A. Kesisova Konstantinos C. Nakos Avgi Tsolou Dimitrios Angelis Joe Lewis Aikaterini Chatzaki Bogos Agianian Athanassios Giannis Maria D. Koffa |
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Affiliation: | 1. Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.; 2. Chemical Biology Core Facility, European Molecular Biology Laboratory, Heidelberg, Germany.; 3. Department of Medicine, Democritus University of Thrace, Alexandroupolis, Greece.; 4. Institute for Organic Chemistry, University of Leipzig, Leipzig, Germany.; University of Saarland Medical School, Germany, |
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Abstract: | Mitotic regulators exhibiting gain of function in tumor cells are considered useful cancer therapeutic targets for the development of small-molecule inhibitors. The human Aurora kinases are a family of such targets. In this study, from a panel of 105 potential small-molecule inhibitors, two compounds Tripolin A and Tripolin B, inhibited Aurora A kinase activity in vitro. In human cells however, only Tripolin A acted as an Aurora A inhibitor. We combined in vitro, in vivo single cell and in silico studies to demonstrate the biological action of Tripolin A, a non-ATP competitive inhibitor. Tripolin A reduced the localization of pAurora A on spindle microtubules (MTs), affected centrosome integrity, spindle formation and length, as well as MT dynamics in interphase, consistent with Aurora A inhibition by RNAi or other specific inhibitors, such as MLN8054 or MLN8237. Interestingly, Tripolin A affected the gradient distribution towards the chromosomes, but not the MT binding of HURP (Hepatoma Up-Regulated Protein), a MT-associated protein (MAP) and substrate of the Aurora A kinase. Therefore Tripolin A reveals a new way of regulating mitotic MT stabilizers through Aurora A phosphorylation. Tripolin A is predicted to bind Aurora A similarly but not identical to MLN8054, therefore it could be used to dissect pathways orchestrated by Aurora kinases as well as a scaffold for further inhibitor development. |
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