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.

Modeling reveals cortical dynein-dependent fluctuations in bipolar spindle length

“…HSET overexpression is prominent in many cancer contexts where its expression corresponds with increased cell proliferation (90,91). This relationship with proliferation is independent of centrosome number, though in cancer contexts where centrosome number is amplified, HSET is additionally required to cluster extra spindle poles into a bipolar spindle (78,(92)(93)(94)(95)(96). We have confirmed that our model captures spindle-pole collapse in the context of high HSET activity (Fig.…”

“…We propose that dynamic changes in bipolar spindle length, driven by cortical dynein activity, contributes to the spindle length requirements for chromosome capture and alignment, with particular relevance to cancer contexts where chromosome number is increased. In cancer contexts where supernumerary centrosome are present, HSET-dependent centrosome clustering promotes bipolar spindle formation [75,76,77,78,66,79]. High HSET levels have also been reported in cancer cells independent of centrosome number, although the functional implications of high HSET activity in this context remains unclear [73,74].…”

“…Cortical dynein is required for spindle bipolarity when HSET activity is high HSET overexpression is prominent in many cancer contexts where its expression corresponds with increased cell proliferation [73,74]. This relationship with proliferation is independent of centrosome number, though in cancer contexts where centrosome number is amplified, HSET is additionally required to cluster extra spindle poles into a bipolar spindle [75,76,77,78,66,79]. To model high HSET activity, we incrementally increased the HSET binding probability from its base level of P H = 0.5.…”

Targeting centrosome amplification, an Achilles' heel of cancer

“…Interestingly, KIFC1 [66–68] and TACC3 [69,70] are also required for acentrosomal spindle assembly in multiple organisms, suggesting that cancer cells may be dependent on these meiotic mechanisms to form bipolar spindles when the centrosome complement of the cell is abnormal. Aurora-A is also required for clustering [32]. This is particularly noteworthy as Aurora-A is a mitotic kinase required for both TACC3 spindle localisation [71,72] and HURP activity [31].…”

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 ]. Recently, it has shown that Aurora‐A inhibition limits centrosome clustering and promotes mitotic multipolarity in cells with supernumerary centrosomes [Navarro‐Serer et al ]. 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 .…”