Functional effects of AKT3 on aurora kinase inhibitorinduced aneuploidy

Kohji Noguchi, Keita Hongama, Shiori Hariki, Yuma Nonomiya, Kazuhiro Katayama, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The suppression of mitotic Aurora kinases (AURKs) byAURK inhibitors frequently causes cytokinetic failure, leading to polyploidy or aneuploidy, indicating the critical role of AURKmediated phosphorylation during cytokinesis. We demonstrate the deregulated expression of AKT3 in Aurora kinase inhibitor (AURKi)-resistant cells, which we established from human colorectal cancer HCT 116 cells. The AKT family, which includes AKT1, -2, and -3, plays multiple roles in antiapoptotic functions and drug resistance and is involved in cell growth and survival pathways. We found that an AKT inhibitor, AZD5363, showed synergistic effect with an AURKi, VX-680, on two AKT3-expressing AURKi-resistant cell lines, and AKT3 knockdown sensitized cells to VX-680. Consistent with these activities, AKT3 expression suppressed AURKi-induced apoptosis and conferred resistance to AURKi. Thus, AKT3 expression affects cell sensitivity to AURKi. Moreover, we found that AKT3 expression suppressed AURKi-induced aneuploidy, and inversely AKT3 knockdown enhanced it. In addition, partial co-localization of AKT3 with AURKB was observed during anaphase. Overall, this study suggests that AKT3 could repress the antiproliferative effects of AURKi, with a novel activity particularly suppressing the aneuploidy induction.

Original languageEnglish
Pages (from-to)1910-1924
Number of pages15
JournalJournal of Biological Chemistry
Volume292
Issue number5
DOIs
Publication statusPublished - 2017 Feb 3

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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