Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53
Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53
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DOI：
10.4161/cc.24573
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发表时间：
2013-04
期刊：
影响因子：
4.3
通讯作者：
M. Sanhaji;F. Louwen;B. Zimmer;N. Kreis;S. Roth;Juping Yuan
中科院分区：
文献类型：
--
作者：
M. Sanhaji;F. Louwen;B. Zimmer;N. Kreis;S. Roth;Juping Yuan
Polo-like kinase1已被确定为最具吸引力的分子癌症治疗靶点之一。事实上，针对该激酶的多种小分子抑制剂已经被开发出来并进行了深入的研究。最近，有报道称，在p53失活的癌细胞中，Plk1抑制所诱导的细胞毒作用增强，这导致了P53失活是Plk1抑制反应的预测标志的假说。在我们之前的基于不同癌细胞系的研究中，我们发现野生型p53的癌细胞与缺失p53的癌细胞相比，通过诱导更多的细胞凋亡而对Plk1的抑制更敏感。在本工作中，我们进一步证明，在不同药物诱导的有丝分裂应激存在下，Plk1抑制剂强烈诱导HCT116 p53+/+细胞凋亡，而HCT116 p53−/−细胞停滞在有丝分裂中，凋亡较少。去除HCT116、P53+/+或U2OS细胞中P53的表达可减少细胞凋亡的诱导。存活的HCT116P53−/−细胞具有较强的DNA损伤和集落形成能力。PLK1抑制与其他抗有丝分裂药联合应用对肿瘤细胞增殖的抑制作用强于Plk1单独抑制作用。综上所述，这些数据强调，功能性的p53通过强烈激活细胞死亡信号通路，单独或联合使用增强了Plk1抑制的有效性。P53缺失的长期后果，例如肿瘤细胞分化程度低或DNA损伤检查点缺陷，是否与Plk1抑制的细胞毒性有关，还需要进一步的研究。
Polo-like kinase 1 has been established as one of the most attractive targets for molecular cancer therapy. In fact, multiple small-molecule inhibitors targeting this kinase have been developed and intensively investigated. Recently, it has been reported that the cytotoxicity induced by Plk1 inhibition is elevated in cancer cells with inactive p53, leading to the hypothesis that inactive p53 is a predictive marker for the response of Plk1 inhibition. In our previous study based on different cancer cell lines, we showed that cancer cells with wild type p53 were more sensitive to Plk1 inhibition by inducing more apoptosis, compared with cancer cells depleted of p53. In the present work, we further demonstrate that in the presence of mitotic stress induced by different agents, Plk1 inhibitors strongly induced apoptosis in HCT116 p53+/+ cells, whereas HCT116 p53−/− cells arrested in mitosis with less apoptosis. Depletion of p53 in HCT116 p53+/+ or U2OS cells reduced the induction of apoptosis. Moreover, the surviving HCT116 p53−/− cells showed DNA damage and a strong capability of colony formation. Plk1 inhibition in combination with other anti-mitotic agents inhibited proliferation of tumor cells more strongly than Plk1 inhibition alone. Taken together, the data underscore that functional p53 strengthens the efficacy of Plk1 inhibition alone or in combination by strongly activating cell death signaling pathways. Further studies are required to investigate if the long-term outcomes of losing p53, such as low differential grade of tumor cells or defective DNA damage checkpoint, are responsible for the cytotoxicity of Plk1 inhibition.