PLK4 is a determinant of temozolomide sensitivity through phosphorylation of IKBKE in glioblastoma.
PLK4 is a determinant of temozolomide sensitivity through phosphorylation of IKBKE in glioblastoma.
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DOI：
10.1016/j.canlet.2018.11.034
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发表时间：
2019-02
期刊：
影响因子：
9.7
通讯作者：
Zuoxin Zhang;Zengguang Wang;Kai Huang;Yan-wei Liu;Cheng Wei;Junhu Zhou;Wei Zhang;Qixue Wang;Hao Liang;An-ling Zhang;Guang-xiu Wang;Y. Zhen;Lei Han
中科院分区：
文献类型：
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作者：
Zuoxin Zhang;Zengguang Wang;Kai Huang;Yan-wei Liu;Cheng Wei;Junhu Zhou;Wei Zhang;Qixue Wang;Hao Liang;An-ling Zhang;Guang-xiu Wang;Y. Zhen;Lei Han
尽管替莫唑胺（TMZ）在临床上取得了成功，但其敏感性仍然是胶质母细胞瘤（GBM）的主要挑战。在这里，我们表明 PLK4 通过调节 IKBKE/NF-κB 轴来影响 TMZ 敏感性。 PLK4 的 mRNA 水平与神经胶质瘤分级进展显着相关，与高级别神经胶质瘤 (HGG) 患者的总生存期 (OS) 呈负相关。进一步的分析表明，PLK4 表达水平低的 GBM 患者比 PLK4 表达水平高的患者从化疗中获得了更大的生存获益。在GBM细胞中，TMZ敏感性因PLK4的异位表达而降低，并因PLK4的耗尽而增强。在 GBM 小鼠模型中，抑制 PLK4 与化疗相结合可减缓肿瘤生长并提供显着的生存益处。此外，PLK4 与 IKBKE 相互作用并使其磷酸化，导致 NF-κB 转录活性增加并抗凋亡。值得注意的是，目前正在进行临床试验的 PLK4 抑制剂 CFI400945 与 TMZ 具有协同作用，可提高患者来源的原发性 GBM 异种移植物中的 TMZ 敏感性。我们的工作描述了影响 GBM 增殖和化疗敏感性的 PLK4-IKBKE 信号轴，并且可以通过治疗靶向增强化疗的抗肿瘤效果。
Despite the clinical success of temozolomide (TMZ), its sensitivity remains a major challenge in glioblastoma (GBM). Here, we show that PLK4 affects TMZ sensitivity by regulating the IKBKE/NF-κB axis. The mRNA level of PLK4 was significantly associated with glioma grade progression and inversely correlated with overall survival (OS) in patients with high-grade gliomas (HGG). Further analyses indicated that GBM patients with low PLK4 expression levels gained greater survival benefits from chemotherapy than did those with high PLK4 expression. In GBM cells, TMZ sensitivity was decreased by ectopic expression of PLK4 and enhanced by depletion of PLK4. In the GBM mice model, inhibiting PLK4 in combination with chemotherapy slowed tumor growth and provided a significant survival benefit. Furthermore, PLK4 interacted with and phosphorylated IKBKE, leading to an increase in NF-κB transcriptional activity and anti-apoptosis. Notably, the PLK4 inhibitor CFI400945, which is currently in clinical trials, had a synergistic effect with TMZ, increasing TMZ sensitivity in xenografts from patient-derived primary GBMs. Our work describes the PLK4-IKBKE signaling axis that influences GBM proliferation and chemosensitivity, and can enhance the anti-tumor effects of chemotherapy via therapeutic targeting.