Induction of p21CIP1 Protein and Cell Cycle Arrest after Inhibition of Aurora B Kinase Is Attributed to Aneuploidy and Reactive Oxygen Species

Abstract

Background: p21 is induced when Aurora B is inhibited. Results: p21-induction after Aurora B inhibition is attributed to aneuploidy and reactive oxygen species. Conclusion: Aneuploidy and ROS mediate cell cycle arrest after Aurora B inhibition by promoting p21-induction. Significance: The study contributes to the understanding of the mechanisms for p21-induction and cell cycle arrest following an aberrant mitosis.

Aurora B Overexpression Causes Aneuploidy and p21Cip1 Repression during Tumor Development

“…Aurora A and Aurora B are known to phosphorylate and inactivate p53 in cultured cells, resulting in decreased expression of its transcriptional targets (24,25,46). Indeed, Aurora B deficiency leads to enhanced expression of p21 Cip1 , resulting in aberrant Cdk activity and cell cycle progression (26,47). These results are also in agreement with an inverse correlation between Aurora B and p21…”

The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

“…A study suggested that phosphorylation of p38 MAPK was induced by ROS following by ZM447439 (a selective inhibitor of Aurora B kinase) treatment, while no change in expression of g-H2AX could be detected. 20 Inhibition of Aurora A induced DNA damage and increased the accumulation of g-H2AX in cancer cells. 18 In this study, treatment of VX680 induced apoptosis and activated H2AX in a dose dependent manner.…”

“…[34][35][36] In recent studies, the activation of p38 MAPK has been suggested to be induced by Aurora B kinase inhibition. 37,38 However, the role of p38 MAPK in VX680-induced effects remains unclear.…”

“…7 Inhibition of Aurora B kinase contributes to the aneuploidy, loss of mitochondrial membrane potential, activation of caspase-9 followed by activation of caspase-3. 20,21 In a preclinical study, the inhibition of Aurora B kinase via AZD1152 was found to inhibit the growth of colon, lung and hematologic tumor xenografts in immunodeficient mice. 22 VX680 inhibits the activities of both the Aurora A and B kinases.…”

Functional Effects of AKT3 on Aurora Kinase Inhibitor-induced Aneuploidy

“…We confirmed that AKT3 suppresses AURKi-induced caspase-9 activation and confers resistance to AURKi, whereas the AURKi-induced accumulation of TP53 and P21 was not abolished by AKT3. A previous study reported that reactive oxygen species (ROS) and p38 MAPK activate P21 in AURKiinduced aneuploid cells (34), and the increased ROS production in aneuploid cells is attributed to high glucose metabolism (35). Intriguingly, the glucose metabolic pathway seems to be altered in our AURKi-resistant clones, because the expressions of the glucose transporter GLUT1 and some glycolysis-regulating enzyme genes were up-regulated in the VX-resistant clones (data not shown).…”