title: Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells.
abstract: The molecular mechanism responsible that determines cell fate after mitotic slippage is unclear. Here we investigate the post-mitotic effects of different mitotic aberrations--misaligned chromosomes produced by CENP-E inhibition and monopolar spindles resulting from Eg5 inhibition. Eg5 inhibition in cells with an impaired spindle assembly checkpoint (SAC) induces polyploidy through cytokinesis failure without a strong anti-proliferative effect. In contrast, CENP-E inhibition causes p53-mediated post-mitotic apoptosis triggered by chromosome missegregation. Pharmacological studies reveal that aneuploidy caused by the CENP-E inhibitor, Compound-A, in SAC-attenuated cells causes substantial proteotoxic stress and DNA damage. Polyploidy caused by the Eg5 inhibitor does not produce this effect. Furthermore, p53-mediated post-mitotic apoptosis is accompanied by aneuploidy-associated DNA damage response and unfolded protein response activation. Because Compound-A causes p53 accumulation and antitumour activity in an SAC-impaired xenograft model, CENP-E inhibitors could be potential anticancer drugs effective against SAC-impaired tumours.
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ohashi
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Momoko
authors.initials: M
authors.lastname: Ohori
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Iwai
authors.affiliation: Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakayama
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Nambu
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Morishita
authors.affiliation: Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: DMPK Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Miyamoto
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Hirayama
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Okaniwa
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Banno
authors.affiliation: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Ishikawa
authors.affiliation: Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kandori
authors.affiliation: DMPK Research Laboratories, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa 251-8555, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Iwata
mesh_terms: D000782:Aneuploidy; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053179:Caspase 7; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005786:Gene Expression Regulation; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors; D059566:M Phase Cell Cycle Checkpoints / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009374:Neoplasms, Experimental; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C470243:KIF11 protein, human; D016159:Tumor Suppressor Protein p53; C068688:centromere protein E; D053148:Caspase 3; D053179:Caspase 7; C521052:Kif11 protein, mouse; D016547:Kinesins