Functional Effects of AKT3 on Aurora Kinase Inhibitor-induced Aneuploidy

Abstract

Edited by Eric R. FearonThe suppression of mitotic Aurora kinases (AURKs) by AURK 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.

IL-10 promoter transactivation by the viral K-RTA protein involves the host-cell transcription factors, specificity proteins 1 and 3

“…Cells were transfected with the plasmid expressing FLAG-K-RTA, using FuGENE HD transfection reagent (Promega) and, on the following day, were fixed with 3.7% formalin/phosphate-buffered saline (PBS) for 10 min at room temperature. Incubation with the antibodies was performed as described previously (55). Briefly, cells were permeabilized, blocked, and incubated with primary and secondary antibodies.…”

Stress-Induced Polyploid Giant Cancer Cells: Unique Way of Formation and Non-Negligible Characteristics

“…Several recent studies have focused on Aurora kinases (AURK). A variety of broad-spectrum or specific Aurora kinases inhibitors (AURKi), including inhibitors targeting on three highly conserved serine/threonine kinases, Aurora A-C, respectively, have been confirmed to induce polyploid cells by regulating mitosis or cell division arrest (80)(81)(82)(83). Since the expression of Aurora kinases, especially Aurora A and B, on centrosomes and chromosomal centromeres is essential for mitosis (89,90), it has received widespread attention that AURK inhibitors have the potential to become a therapeutic target to bring about tumor cell senescence and death.…”