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.
Highlights
RNF8, and the tumor suppressor p53 binding protein 1, 53BP1 by mitotic kinases[2]
Accumulating evidence in the research field of radiation biology has demonstrated that the radiosensitivity of cells depends on the phases of the cell cycle; cells are relatively radioresistant in the late S-phase, but are radiosensitive in the mitotic phase (M-phase)
This fundamental principle prompted us to hypothesize that the small molecule inhibitor of Polo-like kinase 1 (PLK1), TAK-960, which has been reported to cause the mitotic arrest of cancer cells[19], may enhance the cytotoxic effects of radiation
Summary
RNF8, and the tumor suppressor p53 binding protein 1, 53BP1 by mitotic kinases[2]. genes that are responsible for the progression of this cell cycle phase are considered to be potential targets for enhancing the therapeutic effects of radiation. PLK1 was previously shown to be overexpressed in various types of cancers and is known to be responsible for the aberrant proliferation of cancer cells. Another important function of PLK1 is to control DNA damage responses through the regulation of p53 binding protein 1 (53BP1) and claspin activities[8,9]. The intratumoral expression levels of PLK1 have been correlated with the poor prognoses of patients with various types of cancers[10,11,12,13,14,15,16,17,18] These findings justify both the development of PLK1 inhibitors as anti-cancer agents and their application to chemoradiotherapy. For the first time, the radiosensitizing effects of TAK-960 and provided direct evidence for the involvement of mitotic arrest in the radiosensitizing effects of PLK1 blockade using the mutant type of PLK1 mimicking T210 phosphorylation
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