title: Functional Effects of AKT3 on Aurora Kinase Inhibitor-induced Aneuploidy.
abstract: 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.
authors.affiliation: From the Division of Chemotherapy, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. Electronic address: noguchi-kj@pha.keio.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Noguchi
authors.affiliation: From the Division of Chemotherapy, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Hongama
authors.affiliation: From the Division of Chemotherapy, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Hariki
authors.affiliation: From the Division of Chemotherapy, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Nonomiya
authors.affiliation: From the Division of Chemotherapy, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Katayama
authors.affiliation: From the Division of Chemotherapy, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
mesh_terms: D000705:Anaphase / Q000187:drug effects*; D000782:Aneuploidy; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D010879:Piperazines / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D003521:Cyclopropanes; D011720:Pyrazoles
chemical_list: D064107:Aurora Kinase B; D010879:Piperazines; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011758:Pyrroles; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; C491754:AKT3 protein, human; C576921:AURKB protein, human; C575618:capivasertib
keywords: AKT PKB; cancer; cancer biology; cell division; drug resistance; mitosis