Functional Effects of AKT3 on Aurora Kinase Inhibitor-induced Aneuploidy.
The suppression of mitotic Aurora kinases (AURKs) by AURK inhibitors frequently causes cytokinetic failure, leading to polyploidy or aneuploidy, indicating the critical role of AURK-mediated 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.
['Noguchi|Kohji|K|', 'Hongama|Keita|K|', 'Hariki|Shiori|S|', 'Nonomiya|Yuma|Y|', 'Katayama|Kazuhiro|K|', 'Sugimoto|Yoshikazu|Y|']
D000705:Anaphase D000782:Aneuploidy D064107:Aurora Kinase B D015971:Gene Expression Regulation, Enzymologic D015972:Gene Expression Regulation, Neoplastic D057809:HEK293 Cells D006367:HeLa Cells D006801:Humans D061986:MCF-7 Cells D010879:Piperazines D051057:Proto-Oncogene Proteins c-akt D011743:Pyrimidines D011758:Pyrroles
cancer drug resistance AKT PKB cancer biology cell division mitosis