title: MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy.
abstract: Aurora A kinase plays an essential role in the proper assembly and function of the mitotic spindle, as its perturbation causes defects in centrosome separation, spindle pole organization, and chromosome congression. Moreover, Aurora A disruption leads to cell death via a mechanism that involves aneuploidy generation. However, the link between the immediate functional consequences of Aurora A inhibition and the development of aneuploidy is not clearly defined. In this study, we delineate the sequence of events that lead to aneuploidy following Aurora A inhibition using MLN8054, a selective Aurora A small-molecule inhibitor. Human tumor cells treated with MLN8054 show a high incidence of abnormal mitotic spindles, often with unseparated centrosomes. Although these spindle defects result in mitotic delays, cells ultimately divide at a frequency near that of untreated cells. We show that many of the spindles in the dividing cells are bipolar, although they lack centrosomes at one or more spindle poles. MLN8054-treated cells frequently show alignment defects during metaphase, lagging chromosomes in anaphase, and chromatin bridges during telophase. Consistent with the chromosome segregation defects, cells treated with MLN8054 develop aneuploidy over time. Taken together, these results suggest that Aurora A inhibition kills tumor cells through the development of deleterious aneuploidy.
authors: Department of Molecular and Cellular Oncology, Millenium Pharmaceuticals Inc, Cambridge, MA 02139, USA.
authors: Kara
authors: K
authors: Hoar
authors: Arijit
authors: A
authors: Chakravarty
authors: Claudia
authors: C
authors: Rabino
authors: Deborah
authors: D
authors: Wysong
authors: Douglas
authors: D
authors: Bowman
authors: Natalie
authors: N
authors: Roy
authors: Jeffrey A
authors: JA
authors: Ecsedy
mesh_terms: D000782:Aneuploidy; D064127:Aurora Kinases; D001552:Benzazepines / Q000494:pharmacology*; D015153:Blotting, Western; D018385:Centrosome / Q000187:drug effects; D020090:Chromosome Segregation / Q000187:drug effects; D002877:Chromosomes, Human / Q000187:drug effects*; D019084:Fluorescent Antibody Technique, Indirect; D045325:HCT116 Cells; D006801:Humans; D018715:Microscopy, Video; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D008941:Spindle Apparatus / Q000187:drug effects*; D013997:Time Factors
chemical_list: D001552:Benzazepines; C518940:MLN8054; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases