Aneuploidy generates proteotoxic stress and DNA damage concurrently with p53-mediated post-mitotic apoptosis in SAC-impaired cells

Akihiro Ohashi (), Momoko Ohori, Kenichi Iwai, Yusuke Nakayama, Tadahiro Nambu, Daisuke Morishita, Tomohiro Kawamoto, Maki Miyamoto, Takaharu Hirayama, Masanori Okaniwa, Hiroshi Banno, Tomoyasu Ishikawa, Hitoshi Kandori and Kentaro Iwata
Additional contact information
Akihiro Ohashi: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited
Momoko Ohori: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited
Kenichi Iwai: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited
Yusuke Nakayama: Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited
Tadahiro Nambu: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited
Daisuke Morishita: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited
Tomohiro Kawamoto: Biomolecular Research Laboratories, Takeda Pharmaceutical Company Limited
Maki Miyamoto: DMPK Research Laboratories, Takeda Pharmaceutical Company Limited
Takaharu Hirayama: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited
Masanori Okaniwa: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited
Hiroshi Banno: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited
Tomoyasu Ishikawa: Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited
Hitoshi Kandori: Drug Safety Research Laboratories, Takeda Pharmaceutical Company Limited
Kentaro Iwata: DMPK Research Laboratories, Takeda Pharmaceutical Company Limited

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: 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.

Date: 2015
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/ncomms8668 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8668

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms8668

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().