TY - JOUR
T1 - Functional effects of AKT3 on aurora kinase inhibitorinduced aneuploidy
AU - Noguchi, Kohji
AU - Hongama, Keita
AU - Hariki, Shiori
AU - Nonomiya, Yuma
AU - Katayama, Kazuhiro
AU - Sugimoto, Yoshikazu
N1 - Funding Information:
This work was supported in part by Japan Society for the Promotion of Science KAKENHI Grants-in-Aid S1411004, 15K14409, and 26460076. The authors declare that they have no conflicts of interest with the contents of this article.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/2/3
Y1 - 2017/2/3
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M116.747048
DO - 10.1074/jbc.M116.747048
M3 - Article
C2 - 28028179
AN - SCOPUS:85011591357
SN - 0021-9258
VL - 292
SP - 1910
EP - 1924
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 5
ER -
