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SIRT 2 knockdown increases basal autophagy and prevents postslippage death by abnormally prolonging the mitotic arrest that is induced by microtubule inhibitors
Author(s) -
Inoue Toshiaki,
Nakayama Yuji,
Li Yanze,
Matsumori Haruka,
Takahashi Haruka,
Kojima Hirotada,
Wanibuchi Hideki,
Katoh Motonobu,
Oshimura Mitsuo
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12810
Subject(s) - autophagy , sirt2 , mitotic catastrophe , microbiology and biotechnology , mitosis , biology , programmed cell death , gene knockdown , microtubule , cancer research , sirtuin , genetics , apoptosis , gene , acetylation
Mitotic catastrophe, a form of cell death that occurs during mitosis and after mitotic slippage to a tetraploid state, plays important roles in the efficacy of cancer cell killing by microtubule inhibitors ( MTI s). Prolonged mitotic arrest by the spindle assembly checkpoint is a well‐known requirement for mitotic catastrophe, and thus for conferring sensitivity to MTI s. We previously reported that turning off spindle assembly checkpoint activation after a defined period of time is another requirement for efficient postslippage death from a tetraploid state, and we identified SIRT 2, a member of the sirtuin protein family, as a regulator of this process. Here, we investigated whether SIRT 2 regulates basal autophagy and whether, in that case, autophagy regulation by SIRT 2 is required for postslippage death, by analogy with previous insights into SIRT 1 functions in autophagy. We show, by combined knockdown of autophagy genes and SIRT 2 , that SIRT 2 serves this function at least partially by suppressing basal autophagy levels. Notably, increased autophagy induced by rapamycin and mild starvation caused mitotic arrest for an abnormally long period of time in the presence of MTI s, and this was followed by delayed postslippage death, which was also observed in cells with SIRT 2 knockdown. These results underscore a causal association among increased autophagy levels, mitotic arrest for an abnormally long period of time after exposure to MTI s, and resistance to MTI s. Although autophagy acts as a tumor suppressor mechanism, this study highlights its negative aspects, as increased autophagy may cause mitotic catastrophe malfunction. Thus, SIRT 2 offers a novel target for tumor therapy.