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Toxicol Lett. 2018 May 15;288:71-81. doi: 10.1016/j.toxlet.2018.02.019. Epub 2018 Feb 16.

Downregulation of metabotropic glutamate receptor 5 inhibits hepatoma development in a neurotoxin rotenone-induced Parkinson's disease model.

Author information

1
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.
2
Shanxi Academy of Analytical Science, 030006, China.
3
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. Electronic address: hzhang@ccmu.edu.cn.

Abstract

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 (mGlu5) 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 mGlu5. Furthermore, treatment with 2-methyl-6-(phenylethynyl)pyridine (MPEP), a mGlu5 antagonist and knockdown of mGlu5, 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 mGlu5 agonist, (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG) and ROS scavenger, N-acetyl-l-cysteine (NAC). The results indicated that down-regulation of mGlu5 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 mGlu5. The study suggest that negative regulation of mGlu5 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.

KEYWORDS:

Apoptosis; Hepatoma; Metabotropic glutamate receptor 5; Parkinson’s disease; Rotenone

PMID:
29458170
DOI:
10.1016/j.toxlet.2018.02.019
[Indexed for MEDLINE]

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