Inhibition of Cdk2 activity decreases Aurora-A kinase centrosomal localization and prevents centrosome amplification in breast cancer cells

Alexey A. Leontovich, Jeffrey L. Salisbury, Massimiliano Veroux, Tiziano Tallarita, Daniel Billadeau, James McCubrey, James Ingle, Evanthia Galanis, Antonino B. D'Assoro

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Centrosome amplification plays a key role in the origin of chromosomal instability (CIN) during cancer development and progression. In this study, MCF-7 breast cancer cell lines harboring abrogated p53 function (vMCF-7 DNp53) were employed to investigate the relationship between induction of genotoxic stress, activation of cyclin-A/Cdk2 and Aurora-A oncogenic signalings and development of centrosome amplification. Introduction of genotoxic stress in the vMCF-7DNp53 cell line by treatment with hydroxyurea (HU) induced centrosome amplification that was mechanistically linked to Aurora-A kinase activity. In cells carrying defective p53, the develop ment of centrosome amplification also occurred following treatment with another DNA damaging agent, methotrexate. Importantly, we demonstrated that Aurora-A kinase-induced centrosome amplification was mediated by Cdk2 kinase since molecular inhibition of Cdk2 activity by SU9516 suppressed Aurora-A centrosomal localization and consequent centro some amplification. In addition, we employed vMCF-7DRaf-1 cells that display high levels of endogenous cyclin-A and demonstrated that molecular targeting of Aurora-A by Alisertib reduces cyclin-A expression. Taken together, these findings demonstrate a novel positive feed-back loop between cyclin-A/Cdk2 and Aurora-A pathways in the development of centrosome amplification in breast cancer cells. They also provide the translational rationale for targeting 'druggable cell cycle regulators' as an innovative therapeutic strategy to inhibit centrosome amplification and CIN in breast tumors resistant to conventional chemotherapeutic drugs.

Original languageEnglish (US)
Pages (from-to)1785-1788
Number of pages4
JournalOncology reports
Volume29
Issue number5
DOIs
StatePublished - May 2013

Keywords

  • Aurora-A
  • Breast cancer
  • Cdk2
  • Centrosome amplification
  • Genotoxic stress

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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