Tripolin A, a Novel Small-Molecule Inhibitor of Aurora A Kinase, Reveals New Regulation of HURP's Distribution on Microtubules

Iliana A. Kesisova, Konstantinos C. Nakos, Avgi Tsolou, Dimitrios Angelis, Joe Lewis, Aikaterini Chatzaki, Bogos Agianian, Athanassios Giannis, Maria D. Koffa

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere58485
JournalPLoS One
Volume8
Issue number3
DOIs
StatePublished - Mar 13 2013
Externally publishedYes

Fingerprint

Aurora Kinase A
Microtubules
microtubules
phosphotransferases (kinases)
Molecules
Aurora Kinases
centrosomes
hepatoma
Cells
interphase
Centrosome
Phosphorylation
Microtubule-Associated Proteins
phosphorylation
Interphase
proteins
Chromosomes
RNA Interference
OXVW5 compound
cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Kesisova, I. A., Nakos, K. C., Tsolou, A., Angelis, D., Lewis, J., Chatzaki, A., ... Koffa, M. D. (2013). Tripolin A, a Novel Small-Molecule Inhibitor of Aurora A Kinase, Reveals New Regulation of HURP's Distribution on Microtubules. PLoS One, 8(3), [e58485]. https://doi.org/10.1371/journal.pone.0058485

Tripolin A, a Novel Small-Molecule Inhibitor of Aurora A Kinase, Reveals New Regulation of HURP's Distribution on Microtubules. / Kesisova, Iliana A.; Nakos, Konstantinos C.; Tsolou, Avgi; Angelis, Dimitrios; Lewis, Joe; Chatzaki, Aikaterini; Agianian, Bogos; Giannis, Athanassios; Koffa, Maria D.

In: PLoS One, Vol. 8, No. 3, e58485, 13.03.2013.

Research output: Contribution to journalArticle

Kesisova, IA, Nakos, KC, Tsolou, A, Angelis, D, Lewis, J, Chatzaki, A, Agianian, B, Giannis, A & Koffa, MD 2013, 'Tripolin A, a Novel Small-Molecule Inhibitor of Aurora A Kinase, Reveals New Regulation of HURP's Distribution on Microtubules', PLoS One, vol. 8, no. 3, e58485. https://doi.org/10.1371/journal.pone.0058485
Kesisova, Iliana A. ; Nakos, Konstantinos C. ; Tsolou, Avgi ; Angelis, Dimitrios ; Lewis, Joe ; Chatzaki, Aikaterini ; Agianian, Bogos ; Giannis, Athanassios ; Koffa, Maria D. / Tripolin A, a Novel Small-Molecule Inhibitor of Aurora A Kinase, Reveals New Regulation of HURP's Distribution on Microtubules. In: PLoS One. 2013 ; Vol. 8, No. 3.
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