title: Janus face-like effects of Aurora B inhibition: antitumoral mode of action versus induction of aneuploid progeny.
abstract: The mitotic Aurora B kinase is overexpressed in tumors and various inhibitors for Aurora B are currently under clinical assessments. However, when considering Aurora B kinase inhibitors as anticancer drugs, their mode of action and the role of p53 status as a possible predictive factor for response still needs to be investigated. In this study, we analyzed the effects of selective Aurora B inhibition using AZD1152-HQPA/Barasertib (AZD1152) on HCT116 cells, U87-MG, corresponding isogenic p53-deficient cells and a primary glioblastoma cell line. AZD1152 treatment caused polyploidy and non-apoptotic cell death in all cell lines irrespective of p53 status and was accompanied by poly-merotelic kinetochore-microtubule attachments and DNA damage. In p53 wild-type cells a DNA damage response induced an inefficient pseudo-G1 cell cycle arrest, which was not able to halt ongoing endoreplication of cells. Of note, release of tumor cells from AZD1152 resulted in recovery of aneuploid progenies bearing numerical and structural chromosomal aberrations. Yet, AZD1152 treatment enhanced death receptor TRAIL-R2 levels in all tumor cell lines investigated. A concomitant increase of the activating natural killer (NK) cell ligand MIC A/B in p53-deficient cells and an induction of FAS/CD95 in cells containing p53 rendered AZD1152-treated cells more susceptible for NK-cell-mediated lysis. Our study mechanistically explains a p53-independent mode of action of a chemical Aurora B inhibitor and suggests a potential triggering of antitumoral immune responses, following polyploidization of tumor cells, which might constrain recovery of aneuploid tumor cells.
authors: Department of Neurosurgery, Section of Experimental Neurosurgery/Tumor Immunology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany.
authors: Ralf
authors: R
authors: Wiedemuth
authors: Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany, German Cancer Consortium (DKTK), partner site Dresden, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany and.
authors: Barbara
authors: B
authors: Klink
authors: Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima 772-0023, Japan.
authors: Mamoru
authors: M
authors: Fujiwara
authors: Institute for Clinical Genetics, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany, German Cancer Consortium (DKTK), partner site Dresden, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany and.
authors: Evelin
authors: E
authors: Schröck
authors: Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shoubara, Hiroshima 772-0023, Japan.
authors: Masaaki
authors: M
authors: Tatsuka
authors: Department of Neurosurgery, Section of Experimental Neurosurgery/Tumor Immunology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany, German Cancer Consortium (DKTK), partner site Dresden, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany and.
authors: Gabriele
authors: G
authors: Schackert
authors: Department of Neurosurgery, Section of Experimental Neurosurgery/Tumor Immunology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany, German Cancer Consortium (DKTK), partner site Dresden, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany and achim.temme@uniklinikum-dresden.de.
authors: Achim
authors: A
authors: Temme
mesh_terms: D000782:Aneuploidy; D017209:Apoptosis / Q000187:drug effects*; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002869:Chromosome Aberrations / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D010755:Organophosphates / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D010755:Organophosphates; D011799:Quinazolines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C576921:AURKB protein, human; D064107:Aurora Kinase B