Open Access

Aurora kinase A is a possible target of OSU‑03012 to destabilize MYC family proteins

  • Authors:
    • Andres Silva
    • Jennie Wang
    • Sarah Lomahan
    • Tuan-Anh Tran
    • Laura Grenlin
    • Akiko Suganami
    • Yutaka Tamura
    • Naohiko Ikegaki
  • View Affiliations

  • Published online on: July 11, 2014     https://doi.org/10.3892/or.2014.3325
  • Pages: 901-905
  • Copyright: © Silva et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

OSU-03012, a 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitor, destabilizes MYCN and MYC proteins in neuroblastoma cells. However, AKT phosphorylation is barely detectable in neuroblastoma cells under normal culture conditions whether treated with OSU-03012 or not. This observation suggests that PDK1 is not the main target of OSU-03012 to destabilize MYC and MYCN in neuroblastoma cells. In the present study, we explored one of the possible mechanisms by which OSU-03012 destabilizes MYC and MYCN. Since Aurora kinase A is reported to phosphorylate GSK3β, leading to its inactivation, we hypothesized that one of the targets of OSU-03012 is Aurora kinase A. Comparative analysis of OSU-03012 and VX-680, a potent and specific inhibitor of Aurora kinases, showed that both inhibitors destabilized MYC and MYCN and were significantly growth suppressive to neuroblastoma cell lines. In silico molecular docking analysis further showed that the calculated interaction energy between Aurora kinase A and OSU-03012 was -109.901 kcal/mol, which was lower than that (-89.273 kcal/mol) between Aurora kinase A and FXG, an Aurora kinase-specific inhibitor. Finally, an in vitro Aurora kinase A inhibition assay using a recombinant Aurora kinase A showed that OSU-03012 significantly inhibited Aurora kinase A, although it was weaker in potency than that of VX-680. Thus, OSU-03012 has a likelihood of binding to and inhibiting Aurora kinase A in vivo. These results suggest that OSU-03012 affects multiple cellular targets, including Aurora kinase A, to exhibit its growth suppressive and MYC and MYCN-destabilizing effects on neuroblastoma and other cancer cells.
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September-2014
Volume 32 Issue 3

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Silva A, Wang J, Lomahan S, Tran T, Grenlin L, Suganami A, Tamura Y and Ikegaki N: Aurora kinase A is a possible target of OSU‑03012 to destabilize MYC family proteins. Oncol Rep 32: 901-905, 2014
APA
Silva, A., Wang, J., Lomahan, S., Tran, T., Grenlin, L., Suganami, A. ... Ikegaki, N. (2014). Aurora kinase A is a possible target of OSU‑03012 to destabilize MYC family proteins. Oncology Reports, 32, 901-905. https://doi.org/10.3892/or.2014.3325
MLA
Silva, A., Wang, J., Lomahan, S., Tran, T., Grenlin, L., Suganami, A., Tamura, Y., Ikegaki, N."Aurora kinase A is a possible target of OSU‑03012 to destabilize MYC family proteins". Oncology Reports 32.3 (2014): 901-905.
Chicago
Silva, A., Wang, J., Lomahan, S., Tran, T., Grenlin, L., Suganami, A., Tamura, Y., Ikegaki, N."Aurora kinase A is a possible target of OSU‑03012 to destabilize MYC family proteins". Oncology Reports 32, no. 3 (2014): 901-905. https://doi.org/10.3892/or.2014.3325