Abstract A33: Aneuploidy due to inhibition of Aurora B induces p21 through activation of p38 by proteotoxic stress and ROS

Abstract

Abstract Faithful transmission of genomic information to the two daughter cells requires highly coordinated cell cycle regulation. Aurora kinases have been implicated in mediating critical events during mitosis and cytokinesis. Aurora B is the enzymatic component of the chromosome passenger complex (CPC) which shows a characteristic localization during various phases of mitosis. Both the expression level and kinase activity of Aurora B is upregulated in several primary tumors including breast cancer and colon cancer and is associated with poor prognosis. Therefore, Aurora B is an attractive anti-cancer target and several chemical inhibitors of Aurora B are already in clinical trials. Inhibition of Aurora B results in cell cycle arrest. However, the signaling pathways responsible for the phenotypes observed after Aurora B inhibition have not yet been fully explored. We have recently shown that the p53 target gene p21 (CDKN1A) is activated both at protein and mRNA levels after pharmacological inhibition of Aurora B and that p21-activation is dependent on p53 and on the p38 MAP kinase. While the stabilization of p53 and its recruitment to the p21 promoter occur independently of p38, transcriptional elongation of p21 depends on active p38 after Aurora B is inhibited. We further show that partial inhibition of Aurora B is sufficient to induce p21. FISH (Fluorescence in-situ hybridization) assays indicate increased aneuploidy without inhibition of cytokinesis when Aurora B is partially inhibited. Increased aneuploidy is correlated with generation of reactive oxygen species (ROS) and proteotoxic stress, but not with DNA damage. In summary, our data suggest that aneuploidy due to partial inhibition of Aurora B results in proteotoxic stress and in the production of ROS, which contributes to the induction of p21 through activation of p38 MAPK. Significantly, Aurora B inhibitors and drugs that act on aneuploid cells (AICAR and 17AAG) synergize in the inhibition of cell proliferation and in inhibition of transformation. Thus, combining Aurora B inhibitors with drugs that act on aneuploid cells may result in a more effective cancer therapy than Aurora B inhibitors alone. Note: This abstract was not presented at the conference. Citation Format: Geeta Kumari, Tanja Ulrich, Stefan Gaubatz. Aneuploidy due to inhibition of Aurora B induces p21 through activation of p38 by proteotoxic stress and ROS. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr A33.