p53 is not directly relevant to the response of Polo-like kinase 1 inhibitors
p53 is not directly relevant to the response of Polo-like kinase 1 inhibitors
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DOI：
10.4161/cc.11.3.19076
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发表时间：
2012-02-01
期刊：
影响因子：
4.3
通讯作者：
Yuan, Juping
中科院分区：
文献类型：
--
作者：
Sanhaji, Mourad;Kreis, Nina-Naomi;Yuan, Juping
Polo-like kinase1(Plk1)是细胞增殖的基础，它的失控参与了肿瘤的发生。PLK1已被确定为最具吸引力的分子肿瘤治疗靶点之一。事实上，针对Plk1的激酶结构域或Polo-box结合结构域(PBD)的多种小分子抑制剂已经被发现并被深入研究。有趣的是，Plk1缺失比正常细胞影响更多的癌细胞。另有报道称，在P53基因缺陷的癌细胞中，Plk1抑制所诱导的细胞毒作用增强。这些数据导致了这样的假设，即P53可能是Plk1抑制反应的预测标志。在这项研究中，我们证明了具有和不具有功能性P53的癌细胞，包括同基因的结肠癌细胞系HCT116P53(+/+)和HCT116P53(-/-)，乳腺癌细胞系MCF7，肺癌细胞系A549和宫颈癌细胞系HeLa，经抗Plk1的siRNA、激酶结构域抑制剂BI 2536和BI 6727或PBD抑制剂泊洛辛处理后，没有明显的细胞毒性反应。我们认为，P53状态不是Plk1抑制反应的预测因子，至少不是直接预测。然而，丢失p53的长期后果，如基因组不稳定，可能与Plk1抑制的细胞毒性有关。癌细胞的其他环境，如DNA复制/损伤应激、有丝分裂应激和代谢应激，可能使癌细胞的生存更依赖于Plk1功能，是否与Plk1抑制的敏感性有关，还需要进一步的研究。
Polo-like kinase 1 (Plk1) is elementary for cell proliferation, and its deregulation is involved in tumorigenesis. Plk1 has been established as one of the most attractive targets for molecular cancer therapy. In fact, multiple small-molecule inhibitors targeting either the kinase domain or the Polo-box binding domain (PBD) of Plk1 have been identified and intensively investigated. Intriguingly, Plk1 depletion affects more cancer cells than normal cells. It is also reported that the cytotoxicity induced by Plk1 inhibition is elevated in cancer cells with defective p53. The data lead to the hypothesis that p53 might be a predictive marker for the response of Plk1 inhibition. In this study, we demonstrate that there is no obvious different cytotoxic response between cancer cells with and without functional p53, including the isogenic colon cancer cell lines HCT116p53(+/+) and HCT116p53(-/-), breast cancer cell line MCF7, lung cancer cell line A549 and cervical carcinoma cell line HeLa after treatment with either siRNA against Plk1, the kinase domain inhibitors BI 2536 and BI 6727 or the PBD inhibitor Poloxin. We suggest that the p53 status is not a predictor for the response of Plk1 inhibition, at least not directly. Yet, the long-term outcomes of losing p53, such as genome instability, could be associated with the cytotoxicity of Plk1 inhibition. Further studies are required to investigate whether other circumstances of cancer cells, such as DNA replication/damage stress, mitotic stress and metabolic stress, which make possibly the survival of cancer cells more dependent on Plk1 function, are responsible for the sensitivity of Plk1 inhibition.