Department of Emergency, Cardinal Tien Hospital, Hsintien, New Taipei City, Taiwan, ROC.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
Toxicology. 2018 Dec 1;410:65-72. doi: 10.1016/j.tox.2018.09.003. Epub 2018 Sep 8.
Paraquat (PQ) as an herbicide has been demonstrated to impair dopaminergic (DAergic) neurons and highly correlate with the etiology of Parkinson's disease (PD). WNT/β-CATENIN signaling is known for the specification and neurogenesis of midbrain DAergic neurons and implicated as a therapeutic target in treating many diseases, such as cancer and degenerative diseases. LGK974, a WNT pathway inhibitor, is currently under clinical trial for patients with malignancies. Since the exact role of WNT/β-CATENIN signaling in mediating PD is undetermined, LGK974 was used to examine its effect on the PQ-induced cell model of PD. LGK974 attenuated PQ-induced apoptosis and released mitochondrial pro-poptotic molecules in human neuroblastoma SH-SY5Y cell. PQ increased the levels of β-CATENIN, non-phosphorylated (Ser33/37/Thr41) β-CATENIN, and phosphorylated glycogen synthase kinase (GSK)-3α/β. PQ also increased the nuclear translocation of β-CATENIN, which can be attenuated by LKG974. Furthermore, LGK974 attenuated the PQ-induced release of mitochondrial proapoptotic factors and WNT agonist 1-induced cell death. Taken together, we have shown for the first time that LGK974 mediated through the WNT/β-CATENIN pathway to prevent PQ-induced cell death.
百草枯（PQ）作为一种除草剂，已被证明会损害多巴胺能（DAergic）神经元，并与帕金森病（PD）的病因高度相关。WNT/β-CATENIN 信号通路已知可特异性调节中脑 DAergic 神经元的发生和神经发生，并被认为是治疗多种疾病（如癌症和退行性疾病）的治疗靶点。LGK974 是一种 WNT 通路抑制剂，目前正在进行治疗恶性肿瘤患者的临床试验。由于 WNT/β-CATENIN 信号通路在介导 PD 中的确切作用尚未确定，因此使用 LGK974 来检查其对 PQ 诱导的 PD 细胞模型的影响。LGK974 可减轻 PQ 诱导的人神经母细胞瘤 SH-SY5Y 细胞凋亡，并释放线粒体促凋亡分子。PQ 增加了β-CATENIN、非磷酸化（Ser33/37/Thr41）β-CATENIN 和磷酸化糖原合酶激酶（GSK）-3α/β 的水平。PQ 还增加了β-CATENIN 的核转位，这可以被 LGK974 减弱。此外，LGK974 还减轻了 PQ 诱导的线粒体促凋亡因子的释放和 WNT 激动剂 1 诱导的细胞死亡。总之，我们首次表明，LGK974 通过 WNT/β-CATENIN 途径介导，可预防 PQ 诱导的细胞死亡。
