Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes
Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes
复制标题
DOI：
10.1101/gad.1700908
复制
发表时间：
2008-08-15
影响因子：
10.5
通讯作者：
Pellman, David
中科院分区：
文献类型：
--
作者：
Kwon, Mijung;Godinho, Susana A.;Pellman, David
肿瘤细胞中的多个中心体产生多极分裂的可能性，多极分裂可导致非整倍体和细胞死亡。然而，许多癌细胞成功分裂是因为抑制多极有丝分裂的机制。在果蝇S2细胞中进行的全基因组RNAi筛选和在癌细胞中进行的二次分析确定了抑制多极有丝分裂的机制。除了在纺锤体两极组织微管的蛋白质，我们确定了纺锤体组装检查点，皮质肌动蛋白细胞骨架和细胞粘附的新角色。利用活细胞成像和纤连蛋白显微图，我们发现间期细胞的形状和粘附模式可以决定具有额外中心体的细胞随后的有丝分裂的成功。这些发现可以确定癌症选择性治疗靶点：HSET，一种通常非必需的驱动蛋白马达，对某些含有额外中心体的癌细胞的生存力至关重要。因此，癌细胞的形态特征可以与生存的独特遗传要求联系起来。
Multiple centrosomes in tumor cells create the potential for multipolar divisions that can lead to aneuploidy and cell death. Nevertheless, many cancer cells successfully divide because of mechanisms that suppress multipolar mitoses. A genome-wide RNAi screen in Drosophila S2 cells and a secondary analysis in cancer cells defined mechanisms that suppress multipolar mitoses. In addition to proteins that organize microtubules at the spindle poles, we identified novel roles for the spindle assembly checkpoint, cortical actin cytoskeleton, and cell adhesion. Using live cell imaging and fibronectin micropatterns, we found that interphase cell shape and adhesion pattern can determine the success of the subsequent mitosis in cells with extra centrosomes. These findings may identify cancer-selective therapeutic targets: HSET, a normally nonessential kinesin motor, was essential for the viability of certain extra centrosome-containing cancer cells. Thus, morphological features of cancer cells can be linked to unique genetic requirements for survival.