Aurora kinases, aneuploidy and cancer, a coincidence or a real link?

As Aurora kinases are overexpressed in a large number of cancers, and ectopic expression of Aurora generates polyploid cells containing multiple centrosomes, it has been tempting to suggest that Aurora overexpression provokes genetic instability underlying the tumorigenesis. However, examination of the evidence suggests a more complex relationship. Overexpression of Aurora-A readily transforms rat-1 and NIH3T3 cells, but not primary cells, whereas overexpression of Aurora-B induces metastasis after implantation of tumors in nude mice. Why do polyploid cells containing abnormal centrosome numbers induced by Aurora not get eliminated at cell-cycle checkpoints? Does this phenotype determine the origin of cancer or does it only promote tumor progression? Would drugs against aurora family members be of any help for cancer treatment? These and related questions are addressed in this review (which is part of the Chromosome Segregation and Aneuploidy series).

Introduction

The main goal of a mitotic cell is to equally segregate its chromosomes and centrosomes between two daughter cells (Figure 1). As early as 1902, Theodore Boveri predicted that mitotic abnormalities could lead to genetic instability and cancer [1]. Indeed, during mitosis, a spectacular reorganization of the cytoskeleton occurs that builds a bipolar microtubule spindle that assures proper segregation of chromosomes. Mitosis is progressively readied throughout cell-cycle progression: a series of precisely coordinated events must have occurred before the G2–M transition occurs. By the end of S-phase, the cell must have duplicated its centrosome and replicated its DNA. At the end of prophase, the duplicated and matured centrosomes must have become separated. During prometaphase, the two centrosomes and the chromosomes nucleate highly dynamic mitotic microtubules that assemble a bipolar spindle [2]. During progression from prometaphase to metaphase, the chromosomes must become bi-orientated and aligned at the metaphase plate. Bi-orientation is achieved by microtubule-organized attachment of kinetochore pairs to opposite centrosomes. During this process, the mitotic checkpoint is continuously activated; it controls microtubule attachment to the kinetochores and tension. When these two conditions are satisfied, the checkpoint signals are switched off, the chromatids separate and anaphase proceeds. In telophase, nuclear division occurs and the cell undergoes cytokinesis. Finally, each daughter cell receives one set of chromosomes and one centrosome (Box 1).

Considering the complexity of mitosis, it is not surprising that there are many mitotic defects that can lead to the formation of aneuploid daughter cells. An aneuploid cell possesses an altered content of DNA (abnormal number of chromosomes). To give some examples, during mitosis, one can easily imagine at least four ways to obtain an aneuploid cell: (1) incorrect centrosome duplication during interphase that can lead to the formation of multipolar spindles, (2) improper centrosome separation, (3) defective cytokinesis and (4) chromosome mis-orientation (Figure 1).

Progression through mitosis depends on three main regulatory mechanisms: protein localization, proteolysis and phosphorylation. Cdk1 (cyclin-dependent kinase 1 or p34^cdc2), Plk1 (Polo-like kinase), Nek2 (NIMA-related kinase 2) and Aurora kinases are the main mitotic protein kinases known to date [3]. Aurora kinases are involved in centrosome separation and maturation, spindle assembly and stability, chromosome condensation, congression and segregation, and cytokinesis [4]. In mammalian cells, three aurora kinases have been identified, named Aurora-A, -B and -C [3]. They possess a very conserved catalytic domain and an N-terminal domain that varies in sequence and in length 5, 6. It is thought that the different Aurora kinases localize differentially and might perform different functions during mitosis. However, all three human kinases are overexpressed in many types of cancers, in which polyploid cells containing multiple centrosomes are observed. This review discusses how overexpression of aurora kinases provokes the development of such a phenotype, and whether this phenotype is key to oncogenesis. Although many studies of Aurora kinases in organisms such as yeasts, Drosophila, Caenorhabditis elegans and Xenopus have greatly contributed to our understanding of the functions of the kinases, we will only use here the nomenclature Aurora-A, -B and -C and the names of mammalian proteins whenever possible.