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Tetraploidy-linked sensitization to CENP-E inhibition in human cells

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Title: Tetraploidy-linked sensitization to CENP-E inhibition in human cells
Authors: Yoshizawa, Koya Browse this author
Matsura, Akira Browse this author
Shimada, Masaya Browse this author
Ishida-Ishihara, Sumire Browse this author
Sato, Fuyu Browse this author
Yamamoto, Takahiro Browse this author
Yaguchi, Kan Browse this author
Kawamoto, Eiji Browse this author →KAKEN DB
Kuroda, Taruho Browse this author
Matsuo, Kazuya Browse this author →KAKEN DB
Tamaoki, Nobuyuki Browse this author →KAKEN DB
Sakai, Ryuichi Browse this author →KAKEN DB
Shimada, Yasuhito Browse this author →KAKEN DB
Mishra, Mithilesh Browse this author
Uehara, Ryota Browse this author →KAKEN DB
Keywords: chromosome
motor protein
Issue Date: 24-May-2023
Publisher: John Wiley & Sons
Journal Title: Molecular oncology
Publisher DOI: 10.1002/1878-0261.13379
Abstract: 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.
Type: article
Appears in Collections:生命科学院・先端生命科学研究院 (Graduate School of Life Science / Faculty of Advanced Life Science) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 上原 亮太

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