Aurora A inhibition limits centrosome clustering and promotes mitotic catastrophe in cells with supernumerary centrosomes

Abstract

The presence of supernumerary centrosomes is prevalent in cancer, where they promote the formation of transient multipolar mitotic spindles. Active clustering of supernumerary centrosomes enables the formation of a functional bipolar spindle that is competent to complete a bipolar division. Disruption of spindle pole clustering in cancer cells promotes multipolar division and generation of non-proliferative daughter cells with compromised viability. Hence molecular pathways required for spindle pole clustering in cells with supernumerary centrosomes, but dispensable in normal cells, are promising therapeutic targets. Here we demonstrate that Aurora A kinase activity is required for spindle pole clustering in cells with extra centrosomes. While cells with two centrosomes are ultimately able to build a bipolar spindle and proceed through a normal cell division in the presence of Aurora A inhibition, cells with supernumerary centrosomes form multipolar and disorganized spindles that are not competent for chromosome segregation. Instead, following a prolonged mitosis, these cells experience catastrophic divisions that result in grossly aneuploid, and non-proliferative daughter cells. Aurora A inhibition in a panel of Acute Myeloid Leukemia cancer cells has a similarly disparate impact on cells with supernumerary centrosomes, suggesting that centrosome number and spindle polarity may serve as predictive biomarkers for response to therapeutic approaches that target Aurora A kinase function.

Cortical Dynein Drives Centrosome Clustering in Cells with Centrosome Amplification

“…Centrosome clustering is a dynamic process that can take an hour or longer to achieve (Kwon et al, 2008; Navarro-Serer et al, 2019) and analysis of a single time point in mitosis cannot distinguish between a delay versus a deficit in centrosome clustering. To further assess the observed increase in multipolar spindles seen following cortical dynein disruption, cells were additionally treated with the protease inhibitor MG132 prior to assessment of centrosome positioning and spindle structure.…”

Centrosome Defects in Hematological Malignancies: Molecular Mechanisms and Therapeutic Insights

“…2). 101 In their study, AURKA inhibition promoted a panel of AML cells with extra centrosomes to produce multipolar and disorganized spindles, reducing the proliferation and viability of daughter cells. 101 Various transcription factors regulating AURKA have been identified.…”

“…101 In their study, AURKA inhibition promoted a panel of AML cells with extra centrosomes to produce multipolar and disorganized spindles, reducing the proliferation and viability of daughter cells. 101 Various transcription factors regulating AURKA have been identified. Examples include E4TF1, one of the E26 transformation-specific (ETS) family proteins, which can positively regulate AURKA transcriptional levels, 102 and alterations among ETS gene expression are often detected in various hematological malignancies including lymphoma and leukemia.…”

Geraniin Differentially Modulates Chromosome Stability of Colon Cancer and Noncancerous Cells by Oppositely Regulating their Spindle Assembly Checkpoint

“…Although centrosome amplification is a common characteristic of solid and hematological cancers, cancer cells tend to cluster supernumerary centrosomes into two group to enable a bipolar mitosis [Kwon et al 2008]. Recently, it has shown that Aurora-A inhibition limits centrosome clustering and promotes mitotic multipolarity in cells with supernumerary centrosomes [Navarro-Serer et al 2018]. With these in mind, it is therefore tempting to speculate that multipolar spindle and multinucleation induced by geraniin in HCT116 cells may be the combined consequences of centrosome overduplication and declustering resulting from reduced expression of Plk-4, Plk-1, and Aurora-A.…”