Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Medical Research Institute, Wuhan University, Wuhan 430071, China.
Medical Research Institute, Wuhan University, Wuhan 430071, China.
Mol Cell. 2016 Nov 3;64(3):493-506. doi: 10.1016/j.molcel.2016.09.016. Epub 2016 Oct 20.
MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCF ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1. Stabilized N-Myc in turn directly activates PLK1 transcription, constituting a positive feedforward regulatory loop that reinforces Myc-regulated oncogenic programs. Inhibitors of PLK1 preferentially induce potent apoptosis of MYCN-amplified tumor cells from neuroblastoma and small cell lung cancer and synergistically potentiate the therapeutic efficacies of Bcl2 antagonists. These findings reveal a PLK1-Fbw7-Myc signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with Bcl2 antagonists, as potential effective therapeutics for MYC-overexpressing cancers.
MYCN 扩增可预测人类癌症的不良预后和对治疗的耐药性。然而，直接针对 MYCN 编码的蛋白质 N-Myc 的药理学策略仍然难以捉摸。在这里，我们确定了导致 Polo-like kinase-1 (PLK1) 和 N-Myc 之间相互激活的分子机制。PLK1 特异性结合到 SCF 泛素连接酶上，磷酸化它，并促进其自身泛素化和蛋白酶体降解，从而抵消 Fbw7 介导的 N-Myc 和其他底物（包括细胞周期蛋白 E 和 Mcl1）的降解。稳定的 N-Myc 反过来又直接激活 PLK1 转录，构成一个正反馈调节环，增强 Myc 调节的致癌程序。PLK1 抑制剂优先诱导神经母细胞瘤和小细胞肺癌中 MYCN 扩增肿瘤细胞的强烈凋亡，并与 Bcl2 拮抗剂协同增强治疗效果。这些发现揭示了一个 PLK1-Fbw7-Myc 信号通路，它是肿瘤发生的基础，并验证了 PLK1 抑制剂，单独或与 Bcl2 拮抗剂联合使用，作为治疗 MYC 过表达癌症的潜在有效疗法。
