PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase.
PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase.
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DOI：
10.1038/srep15666
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发表时间：
2015-10-27
影响因子：
4.6
通讯作者：
Harada H
中科院分区：
文献类型：
--
作者：
Inoue M;Yoshimura M;Kobayashi M;Morinibu A;Itasaka S;Hiraoka M;Harada H
电离辐射的细胞毒性依赖于细胞周期时相，因此，通过对电离辐射的药理调控，特别是在辐射敏感的有丝分裂期(M期)诱导细胞周期停滞，已被尝试用于有效的放射治疗。Polo-like kinase1(PLK1)是一种丝氨酸/苏氨酸激酶，在有丝分裂过程中发挥作用，目前被认为是放射增敏的潜在靶点。在此，我们使用PLK1的新型小分子抑制剂TAK-960研究了PLK1阻断是否通过调节癌细胞的细胞周期时相来增强辐射的细胞毒效应。TAK-960在体外表现出放射增敏作用，尤其是在增加M期细胞比例的情况下。当提供的时间不足以诱导有丝分裂停止时，Tak-960不会使癌细胞对辐射敏感。PLK1突变体PLK1-R136G和T210D的过表达可取消TAK-960介导的有丝分裂细胞比例的增加，从而消除了TAK-960的辐射增敏作用。肿瘤生长延迟实验还表明，TAK-960的放射增敏作用依赖于M期细胞比例的增加。这些结果为以PLK1为靶点进行放射增敏提供了合理的依据，认为M期停滞的治疗时间窗是放射治疗的最佳时机。
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.