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Tetraploidy-linked sensitization to CENP-E inhibition in human cells.
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.
Afiliação
  • Yoshizawa K; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  • Matsura A; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  • Shimada M; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  • Ishida-Ishihara S; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  • Sato F; Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan.
  • Yamamoto T; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  • Yaguchi K; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  • Kawamoto E; Graduate School of Life Science, Hokkaido University, Sapporo, Japan.
  • Kuroda T; Graduate School of Medicine, Mie University, Tsu, Japan.
  • Matsuo K; Graduate School of Medicine, Mie University, Tsu, Japan.
  • Tamaoki N; Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Kyoto, Japan.
  • Sakai R; Research Institute for Electronic Science, Hokkaido University, Sapporo, Japan.
  • Shimada Y; Graduate School and Faculty of Fisheries Sciences, Hokkaido University, Sapporo, Japan.
  • Mishra M; Department of Integrative Pharmacology, Mie University Graduate School of Medicine, Tsu, Japan.
  • Uehara R; Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
Mol Oncol ; 17(6): 1148-1166, 2023 Jun.
Article em En | MEDLINE | ID: mdl-36688680
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Cromossômicas não Histona / Tetraploidia / Neoplasias Limite: Humans Idioma: En Revista: Mol Oncol Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Cromossômicas não Histona / Tetraploidia / Neoplasias Limite: Humans Idioma: En Revista: Mol Oncol Ano de publicação: 2023 Tipo de documento: Article