Xi Shao-Song, Bai Xiao-Xu, Gu Li, Bao Li-Hui, Yang Hui-Min, An Wei, Wang Xiao-Min, Zhang Hong
Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China.
Department of Cell Biology, School of Basic Medical Sciences, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing 100069, China.
Pharmacol Res. 2017 Jul;121:145-157. doi: 10.1016/j.phrs.2017.04.026. Epub 2017 Apr 26.
Numerous epidemiological studies suggested that there is a variable cancer risk in patients with Parkinson's disease (PD). However, the underlying mechanisms remain unclear. In the present study, the role of metabotropic glutamate receptor 5 (mGluR5) has been investigated in 6-hydroxydopamine (6-OHDA)-induced PD combined with liver cancer both in vitro and in vivo. We found that PD cellular model from 6-OHDA-lesioned MN9D cells suppressed the growth, migration, and invasion of Hepa1-6 cells via down-regulation of mGluR5-mediated ERK and Akt pathway. The application of 2-methyl-6-(phenylethyl)-pyridine and knockdown of mGluR5 further decreased the effect on Hepa-1-6 cells when co-cultured with conditioned media. The effect was increased by (S)-3,5-dihydroxyphenylglycine and overexpression of mGluR5. Moreover, more release of glutamate from 6-OHDA-lesioned MN9D cells suppressed mGluR5-mediated effect of Hepa1-6 cells. Application of riluzole eliminated the increased glutamate release induced by 6-OHDA in MN9D cells and aggravated the suppressive effect on Hepa-1-6 cells. In addition, the growth of implanted liver cancer was inhibited in 6-OHDA induced PD-like rats, and was associated with increased glutamate release in the serum and down-regulation of mGluR5 in tumor tissue. Collectively, these results indicate that selective antagonism of glutamate and mGluR5 has a potentially beneficial effect in both liver cancer and PD, and thus may provide more understanding for the clinical investigation and further an additional therapeutic target for these two diseases.
大量流行病学研究表明，帕金森病（PD）患者患癌风险存在差异。然而，其潜在机制仍不清楚。在本研究中，已在体外和体内研究了代谢型谷氨酸受体5（mGluR5）在6-羟基多巴胺（6-OHDA）诱导的PD合并肝癌中的作用。我们发现，6-OHDA损伤的MN9D细胞建立的PD细胞模型通过下调mGluR5介导的ERK和Akt通路，抑制了Hepa1-6细胞的生长、迁移和侵袭。当与条件培养基共培养时，应用2-甲基-6-（苯乙基）吡啶和敲低mGluR5进一步降低了对Hepa-1-6细胞的影响。（S）-3,5-二羟基苯甘氨酸和mGluR5的过表达增强了这种作用。此外，6-OHDA损伤的MN9D细胞释放更多的谷氨酸抑制了Hepa1-6细胞的mGluR5介导的作用。应用利鲁唑消除了6-OHDA诱导的MN9D细胞谷氨酸释放增加，并加重了对Hepa-1-6细胞的抑制作用。此外，6-OHDA诱导的PD样大鼠体内植入肝癌的生长受到抑制，这与血清中谷氨酸释放增加和肿瘤组织中mGluR5下调有关。总体而言，这些结果表明，谷氨酸和mGluR5的选择性拮抗作用对肝癌和PD都有潜在的有益影响，因此可能为这两种疾病的临床研究提供更多理解，并进一步为这两种疾病提供额外的治疗靶点。
