Bai Xiao Xu, Gu Li, Yang Hui Min, Xi Shao Song, Xia Ning, Zhang Song, Zhang Hong
Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorder, Ministry of Education, Capital Medical University, Beijing 100069, China.
Shanxi Academy of Analytical Science, 030006, China.
Toxicol Lett. 2018 May 15;288:71-81. doi: 10.1016/j.toxlet.2018.02.019. Epub 2018 Feb 16.
Clinical epidemiological studies have shown that there is a link between Parkinson's disease (PD) and cancer, but how PD regulates cancer development remains unknown. In our study, the effect of metabotropic glutamate receptor 5 (mGlu) on hepatoma was explored in a rotenone-induced PD model both in vitro and in vivo. We found that conditioned media derived from MN9D dopaminergic neuronal cells by rotenone-induced toxicity inhibited the growth, migration, invasion and promoted apoptosis of Hepa1-6 cells, which corresponded with decreased expression of mGlu. Furthermore, treatment with 2-methyl-6-(phenylethynyl)pyridine (MPEP), a mGlu antagonist and knockdown of mGlu, further reduced ATP levels and migration distance, and increased cleavage of caspase-3 in Hepa1-6 cells. Additionally, we found that conditioned media derived from rotenone-treated MN9D dopaminergic neuronal cells enhanced reactive oxygen species (ROS) generation and JNK phosphorylation, which could be further increased by MPEP treatment, and attenuated by mGlu agonist, (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) and ROS scavenger, N-acetyl-l-cysteine (NAC). The results indicated that down-regulation of mGlu promoted cell apoptosis through the intracellular ROS/JNK signaling pathway in a rotenone-induced cellular PD model. These findings were confirmed in vivo in a rotenone-induced rat model of PD combined with diethylnitrosamine (DEN)-induced hepatoma. Expression of Ki67 was decreased, and the levels of caspase-3 and p-JNK were increased in this model, which was accompanied by a decrease in protein expression of mGlu. The study suggest that negative regulation of mGlu may inhibit hepatoma development in a rotenone-induced PD model, and as such may help with our further understanding of the correlation between PD and cancer.
临床流行病学研究表明，帕金森病（PD）与癌症之间存在联系，但PD如何调节癌症发展仍不清楚。在我们的研究中，在体外和体内的鱼藤酮诱导的PD模型中探讨了代谢型谷氨酸受体5（mGlu）对肝癌的影响。我们发现，鱼藤酮诱导毒性作用下的MN9D多巴胺能神经元细胞的条件培养基抑制了Hepa1-6细胞的生长、迁移、侵袭并促进其凋亡，这与mGlu表达降低相对应。此外，用mGlu拮抗剂2-甲基-6-（苯乙炔基）吡啶（MPEP）处理以及敲低mGlu，进一步降低了Hepa1-6细胞中的ATP水平和迁移距离，并增加了caspase-3的裂解。此外，我们发现鱼藤酮处理的MN9D多巴胺能神经元细胞的条件培养基增强了活性氧（ROS）的生成和JNK磷酸化，MPEP处理可使其进一步增加，而mGlu激动剂（RS）-2-氯-5-羟基苯甘氨酸（CHPG）和ROS清除剂N-乙酰-L-半胱氨酸（NAC）可使其减弱。结果表明，在鱼藤酮诱导的细胞PD模型中，mGlu的下调通过细胞内ROS/JNK信号通路促进细胞凋亡。这些发现在体内的鱼藤酮诱导的PD大鼠模型与二乙基亚硝胺（DEN）诱导的肝癌模型中得到了证实。在该模型中，Ki67的表达降低，caspase-3和p-JNK的水平升高，同时伴有mGlu蛋白表达的降低。该研究表明，在鱼藤酮诱导的PD模型中，mGlu的负调控可能抑制肝癌发展，因此可能有助于我们进一步了解PD与癌症之间的相关性。
