Article (Scientific journals)
Tripolin A, a Novel Small-Molecule Inhibitor of Aurora A Kinase, Reveals New Regulation of HURP’s Distribution on Microtubules
KOFFA, Maria; Giannis, Athanassios; Kesisova, Iliana A. et al.
2013In PLoS ONE, 8 (3)
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Keywords :
Drug Discovery; HeLa Cells; Humans; Hydroquinones; Indoles; Microtubules; Mitosis; Protein Kinase Inhibitors; Protein Transport; Protein-Serine-Threonine Kinases
Abstract :
[en] 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. © 2013 Kesisova et al.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
KOFFA, Maria ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Giannis, Athanassios
Kesisova, Iliana A.
Nakos, Konstantinos C.
Tsolou, Avgi
Angelis, Dimitrios
Lewis, Joe
Chatzaki, Aikaterini
Agianian, Bogos
External co-authors :
Language :
Title :
Tripolin A, a Novel Small-Molecule Inhibitor of Aurora A Kinase, Reveals New Regulation of HURP’s Distribution on Microtubules
Publication date :
13 March 2013
Journal title :
Publisher :
Public Library of Science, United States - California
Volume :
Issue :
Peer reviewed :
Peer Reviewed verified by ORBi
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