title: Antiproliferative Fate of the Tetraploid Formed after Mitotic Slippage and Its Promotion; A Novel Target for Cancer Therapy Based on Microtubule Poisons.
abstract: Microtubule poisons inhibit spindle function, leading to activation of spindle assembly checkpoint (SAC) and mitotic arrest. Cell death occurring in prolonged mitosis is the first target of microtubule poisons in cancer therapies. However, even in the presence of microtubule poisons, SAC and mitotic arrest are not permanent, and the surviving cells exit the mitosis without cytokinesis (mitotic slippage), becoming tetraploid. Another target of microtubule poisons-based cancer therapy is antiproliferative fate after mitotic slippage. The ultimate goal of both the microtubule poisons-based cancer therapies involves the induction of a mechanism defined as mitotic catastrophe, which is a bona fide intrinsic oncosuppressive mechanism that senses mitotic failure and responds by driving a cell to an irreversible antiproliferative fate of death or senescence. This mechanism of antiproliferative fate after mitotic slippage is not as well understood. We provide an overview of mitotic catastrophe, and explain new insights underscoring a causal association between basal autophagy levels and antiproliferative fate after mitotic slippage, and propose possible improved strategies. Additionally, we discuss nuclear alterations characterizing the mitotic catastrophe (micronuclei, multinuclei) after mitotic slippage, and a possible new type of nuclear alteration (clustered micronuclei).
authors.affiliation: Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan. yujin@med.tottori-u.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakayama
authors.affiliation: Division of Human Genome Science, Department of Molecular and Cellular Biology, School of Life Sciences, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan. toshiaki.inoue.nishida@gmail.com.|Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan. toshiaki.inoue.nishida@gmail.com.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Inoue
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D009369:Neoplasms / Q000473:pathology*; D057891:Tetraploidy
keywords: antiproliferative fate; basal autophagy; cell death during mitotic arrest; chemoresistance; clustered micronuclei; micronuclei; mitotic catastrophe; mitotic slippage; spindle assembly checkpoint; tetraploid