MLN8054, a small-molecule inhibitor of Aurora A, causes spindle pole and chromosome congression defects leading to aneuploidy.
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.
Hoar
Kara
K
Department of Molecular and Cellular Oncology, Millenium Pharmaceuticals Inc, Cambridge, MA 02139, USA.
Chakravarty
Arijit
A
Rabino
Claudia
C
Wysong
Deborah
D
Bowman
Douglas
D
Roy
Natalie
N
Ecsedy
Jeffrey A
JA
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
D001552:Benzazepines; C518940:MLN8054; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases