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Title: PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase
Authors: Inoue, Minoru  orcid https://orcid.org/0000-0002-6312-6757 (unconfirmed)
Yoshimura, Michio  kyouindb  KAKEN_id
Kobayashi, Minoru  kyouindb  KAKEN_id
Morinibu, Akiyo
Itasaka, Satoshi
Hiraoka, Masahiro
Harada, Hiroshi  kyouindb  KAKEN_id  orcid https://orcid.org/0000-0001-7507-3173 (unconfirmed)
Author's alias: 吉村, 通央
平岡, 眞寛
原田, 浩
Issue Date: 27-Oct-2015
Publisher: Nature Publishing Group
Journal title: Scientific Reports
Volume: 5
Thesis number: 15666
Abstract: The cytotoxicity of ionizing radiation depends on the cell cycle phase; therefore, its pharmacological manipulation, especially the induction of cell cycle arrest at the radiosensitive mitotic-phase (M-phase), has been attempted for effective radiation therapy. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that functions in mitotic progression, and is now recognized as a potential target for radiosensitization. We herein investigated whether PLK1 blockade enhanced the cytotoxic effects of radiation by modulating cell cycle phases of cancer cells using the novel small molecule inhibitor of PLK1, TAK-960. The TAK-960 treatment exhibited radiosensitizing effects in vitro, especially when it increased the proportion of M-phase cells. TAK-960 did not sensitize cancer cells to radiation when an insufficient amount of time was provided to induce mitotic arrest. The overexpression of a PLK1 mutant, PLK1-R136G&T210D, which was confirmed to cancel the TAK-960-mediated increase in the proportion of mitotic cells, abrogated the radiosensitizing effects of TAK-960. A tumor growth delay assay also demonstrated that the radiosensitizing effects of TAK-960 depended on an increase in the proportion of M-phase cells. These results provide a rational basis for targeting PLK1 for radiosensitization when considering the therapeutic time window for M-phase arrest as the best timing for radiation treatments.
Rights: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
URI: http://hdl.handle.net/2433/210572
DOI(Published Version): 10.1038/srep15666
Appears in Collections:Journal Articles

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