Navarro-Serer Bernat, Childers Eva P, Hermance Nicole M, Mercadante Dayna, Manning Amity L
Worcester Polytechnic Institute, Department of Biology and Biotechnology, Worcester, MA, USA.
Oncotarget. 2019 Feb 26;10(17):1649-1659. doi: 10.18632/oncotarget.26714.
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.
多余中心体的存在在癌症中很普遍，它们会促进瞬时多极有丝分裂纺锤体的形成。多余中心体的主动聚集能够形成一个有功能的双极纺锤体，从而完成双极分裂。癌细胞中纺锤体极聚集的破坏会促进多极分裂，并产生活力受损的非增殖性子细胞。因此，多余中心体的细胞中纺锤体极聚集所需的分子途径，在正常细胞中并非必需，是很有前景的治疗靶点。在这里，我们证明了极光激酶A的活性是多余中心体细胞中纺锤体极聚集所必需的。虽然在有两个中心体的细胞中，在极光激酶A受到抑制的情况下最终能够构建双极纺锤体并进行正常的细胞分裂，但有多余中心体的细胞会形成多极且无序的纺锤体，无法进行染色体分离。相反，经过长时间的有丝分裂后，这些细胞会经历灾难性分裂，导致产生严重非整倍体且无增殖能力的子细胞。在一组急性髓系白血病癌细胞中抑制极光激酶A，对有多余中心体的细胞也有类似的不同影响，这表明中心体数量和纺锤体极性可能作为预测生物标志物，用于预测对靶向极光激酶A功能的治疗方法产生反应。
