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首页> 外文期刊>Cell cycle >CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner
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CDK1 inhibition sensitizes normal cells to DNA damage in a cell cycle dependent manner

机译：CDK1抑制使正常细胞敏感到细胞周期依赖性方式的DNA损伤

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摘要

Cyclin-dependent kinase 1 (CDK1) orchestrates the transition from the G2 phase into mitosis and as cancer cells often display enhanced CDK1 activity, it has been proposed as a tumor specific anti-cancer target. Here we show that the effects of CDK1 inhibition are not restricted to tumor cells but can also reduce viability in non-cancer cells and sensitize them to radiation in a cell cycle dependent manner.Radiosensitization by the specific CDK1 inhibitor, RO-3306, was determined by colony formation assays in three tumor lines (HeLa, T24, SQ20B) and three non-cancer lines (HFL1, MRC-5, RPE). Initial results showed that CDK1 inhibition radiosensitized tumor cells, but did not sensitize normal fibroblasts and epithelial cells in colony formation assays despite effective inhibition of CDK1 signaling. Further investigation showed that normal cells were less sensitive to CDK1 inhibition because they remained predominantly in G1 for a prolonged period when plated in colony formation assays. In contrast, inhibiting CDK1 a day after plating, when the cells were going through G2/M phase, reduced their clonogenic survival both with and without radiation. Our finding that inhibition of CDK1 can damage normal cells in a cell cycle dependent manner indicates that targeting CDK1 in cancer patients may lead to toxicity in normal proliferating cells. Furthermore, our finding that cell cycle progression becomes easily stalled in non-cancer cells under normal culture conditions has general implications for testing anti-cancer agents in these cells.
机译：细胞周期素依赖性激酶1（CDK1）协调了从G2期到有丝分裂的转变，由于癌细胞通常表现出增强的CDK1活性，它被认为是肿瘤特异性抗癌靶点。在这里，我们表明CDK1抑制的作用不仅限于肿瘤细胞，还可以降低非癌细胞的生存能力，并以细胞周期依赖的方式使其对辐射敏感。通过对三种肿瘤细胞系（HeLa、T24、SQ20B）和三种非肿瘤细胞系（HFL1、MRC-5、RPE）的集落形成试验，确定了特异性CDK1抑制剂RO-3306的放射增敏作用。初步结果表明，CDK1抑制可使肿瘤细胞放射增敏，但在集落形成试验中，尽管CDK1信号受到有效抑制，但对正常成纤维细胞和上皮细胞没有增敏作用。进一步的研究表明，正常细胞对CDK1抑制的敏感性较低，因为在菌落形成试验中，正常细胞在较长时间内主要停留在G1期。相比之下，当细胞处于G2/M期时，在电镀后一天抑制CDK1，在有无辐射的情况下都会降低其克隆存活率。我们发现，抑制CDK1可以以细胞周期依赖的方式损害正常细胞，这表明针对癌症患者的CDK1可能导致正常增殖细胞的毒性。此外，我们发现在正常培养条件下，非癌细胞中的细胞周期进展很容易停滞，这对在这些细胞中检测抗癌药物具有普遍意义。

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