Tetraploidy-linked sensitization to CENP-E inhibition in human cells.
Tetraploidy-linked sensitization to CENP-E inhibition in human cells.
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DOI：
10.1002/1878-0261.13379
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发表时间：
2023-06
影响因子：
6.6
通讯作者：
Uehara, Ryota
中科院分区：
文献类型：
--
作者：
Yoshizawa, Koya;Matsura, Akira;Shimada, Masaya;Ishida-Ishihara, Sumire;Sato, Fuyu;Yamamoto, Takahiro;Yaguchi, Kan;Kawamoto, Eiji;Kuroda, Taruho;Matsuo, Kazuya;Tamaoki, Nobuyuki;Sakai, Ryuichi;Shimada, Yasuhito;Mishra, Mithilesh;Uehara, Ryota
四倍体是癌细胞的标志，四倍体选择性细胞生长抑制是靶向癌症治疗的潜在策略。然而，四倍体细胞对抗增殖治疗的敏感性与正常二倍体细胞的差异在很大程度上仍然未知。在这项研究中，我们发现四倍体细胞明显比二倍体更容易受到有丝分裂驱动蛋白（CENP‐E）抑制剂的影响。在最佳条件下，在二倍体-四倍体共培养中，使用CENP - E抑制剂优先减少四倍体细胞的数量。实时成像显示，在中等程度的CENP - E抑制下，四倍体相关的不可解染色体错偶增加导致四倍体比二倍体有丝分裂延迟更长。有丝分裂阻滞的时间间隔导致内聚疲劳和随后的细胞死亡，特别是在四倍体中，导致四倍体选择性细胞生长抑制。相比之下，微管稳定化合物紫杉醇通过加重纺锤体多极化引起四倍体选择性抑制。我们还发现，在更广泛的细胞系中，用CENP‐E抑制剂治疗在四倍体选择性方面比紫杉醇具有更好的普遍性。我们的研究结果强调了CENP - E抑制剂在四倍体选择性抑制中的独特特性，以及它们在开发四倍体靶向癌症干预措施中的潜在应用。通过全基因组复制产生的四倍体是癌症的标志。在不同的细胞背景下，有丝分裂动力蛋白CENP‐E抑制剂比二倍体抑制剂更优先抑制四倍体细胞。对比成像显示，四倍体相关的染色体错位加重、有丝分裂延迟/突变和随后的细胞死亡，在CENP‐E抑制下，证明了细胞分裂控制的“阿喀喀斯之踵”，染色体数量急剧增加。
Tetraploidy is a hallmark of cancer cells, and tetraploidy‐selective cell growth suppression is a potential strategy for targeted cancer therapy. However, how tetraploid cells differ from normal diploids in their sensitivity to anti‐proliferative treatments remains largely unknown. In this study, we found that tetraploid cells are significantly more susceptible to inhibitors of a mitotic kinesin (CENP‐E) than are diploids. Treatment with a CENP‐E inhibitor preferentially diminished the tetraploid cell population in a diploid–tetraploid co‐culture at optimum conditions. Live imaging revealed that a tetraploidy‐linked increase in unsolvable chromosome misalignment caused substantially longer mitotic delay in tetraploids than in diploids upon moderate CENP‐E inhibition. This time gap of mitotic arrest resulted in cohesion fatigue and subsequent cell death, specifically in tetraploids, leading to tetraploidy‐selective cell growth suppression. In contrast, the microtubule‐stabilizing compound paclitaxel caused tetraploidy‐selective suppression through the aggravation of spindle multipolarization. We also found that treatment with a CENP‐E inhibitor had superior generality to paclitaxel in its tetraploidy selectivity across a broader spectrum of cell lines. Our results highlight the unique properties of CENP‐E inhibitors in tetraploidy‐selective suppression and their potential use in the development of tetraploidy‐targeting interventions in cancer. Tetraploidy arising through whole‐genome duplication is a cancer hallmark. Inhibitors of a mitotic kinesin CENP‐E preferentially suppress tetraploid cells over diploid counterparts with superior generality across different cellular backgrounds. Comparative imaging reveals tetraploidy‐linked aggravation of chromosome misalignment, mitotic delay/catastrophe and subsequent cell death upon CENP‐E inhibition, demonstrating the ‘Achilles' heel' of cell division control with drastically increased chromosome number.
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影响因子：
7
作者：
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通讯作者：
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影响因子：
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