Upregulation of Parkinson's disease-associated protein alpha-synuclein suppresses tumorigenesis via interaction with mGluR5 and gamma-synuclein in liver cancer.

Numerous epidemiological studies suggest a link between Parkinson's disease (PD) and cancer, indicating that PD-associated proteins may mediate the development of cancer. Here, we investigated a potential role of PD-associated protein α-synuclein in regulating liver cancer progression in vivo and in vitro. We found the negative correlation of α-synuclein with metabotropic glutamate receptor 5 (mGluR5) and γ-synuclein by analyzing the data from The Cancer Genome Atlas database, liver cancer patients and hepatoma cells with overexpressed α-synuclein. Moreover, upregulated α-synuclein suppressed the growth, migration, and invasion. α-synuclein was found to associate with mGluR5 and γ-synuclein, and the truncated N-terminal of α-synuclein was essential for the interaction. Furthermore, overexpressed α-synuclein exerted the inhibitory effect on hepatoma cells through the degradation of mGluR5 and γ-synuclein via α-synuclein-dependent autophagy-lysosomal pathway (ALP). Consistently, in vivo experiments with rotenone-induced rat model of PD also confirmed that, upregulated α-synuclein in liver cancer tissues through targeting on mGluR5/α-synuclein/γ-synuclein complex inhibited tumorigenesis involving in ALP-dependent degradation of mGluR5 and γ-synuclein. These findings give an insight into an important role of PD-associated protein α-synuclein accompanied by the complex of mGluR5/α-synuclein/γ-synuclein in distant communications between PD and liver cancer, and provide a new strategy in therapeutics for the treatment of liver cancer.

The Parkinson's disease-associated protein α-synuclein inhibits hepatoma by exosome delivery.

Numerous epidemiological studies suggest a link between Parkinson's disease (PD) and cancer. However, their relevant pathogenesis is not clear. In the present study, we investigated the potential role of exosome-delivered α-synuclein (α-syn) in the regulation between PD and liver cancer. We cultured hepatocellular carcinoma (HCC) cells with exosomes derived from conditioned medium of the PD cellular model, and injected exosomes enriched with α-syn into the striatum of a liver cancer rat model. We found that α-syn-contained exosomes from the rotenone-induced cellular model of PD suppressed the growth, migration, and invasion of HCC cells. Integrin αVß5 in exosomes from the rotenone-induced PD model was higher than that in the control, resulting in more α-syn-contained exosomes being taken up by HCC cells. Consistently, in vivo experiments with rat models also confirmed exosome-delivered α-syn inhibited liver cancer. These findings illustrate the important role of PD-associated protein α-syn inhibiting hepatoma by exosome delivery, suggesting a new mechanism underlying the link between these two diseases and therapeutics of liver cancer.

Inhibition of Wnt/ß-catenin signaling attenuates axonal degeneration in models of Parkinson's disease.

There are currently no treatments to delay or prevent Parkinson's disease (PD), and protective treatments require early administration. Targeting axonal degeneration in early PD could have an important clinical effect; however, the underlying molecular mechanisms controlling axonal degeneration in PD are not fully understood. Here, we studied the role of Wnt/ß-catenin signaling in axonal degeneration induced by 6-hydroxydopamine (6-OHDA) or overexpression of alpha-synuclein (α-Syn) in vitro and in vivo. We found that the levels of both ß-catenin and p-S9-glycogen synthase kinase-3ß (GSK-3ß) increased and the levels of phosphorylated ß-catenin (p-ß-catenin) decreased during 6-OHDA-induced axonal degeneration and that the inhibitors of the Wnt/ß-catenin pathway IWR-1 and Dickkopf-1 (DKK-1) attenuated the degenerative process in primary neurons in vitro. Furthermore, IWR-1 enhanced the increase of LC3-II levels and the decrease of p62 triggered by 6-OHDA treatment, whereas the autophagy inhibitor 3-Methyladenine (3-MA) alleviated the protective effect of IWR-1 on axons in vitro. Consistent with the in vitro findings, both ß-catenin and p-S9-GSK-3ß were upregulated in a 6-OHDA-induced rat PD model, and blocking the Wnt/ß-catenin pathway with DKK-1 attenuated the degeneration of dopaminergic axons at an early time point in vivo. The protective effect of inhibition of Wnt/ß-catenin signaling was further confirmed in an α-Syn overexpression-induced animal models of PD. Taken together, these data indicate that the Wnt/ß-catenin pathway is involved axonal degeneration in PD, and suggest that Wnt/ß-catenin pathway inhibitors have the therapeutic potential for the prevention of PD.

Blocked metabotropic glutamate receptor 5 enhances chemosensitivity in hepatocellular carcinoma and attenuates chemotoxicity in the normal liver by regulating DNA damage.

DNA damaging agents are used as chemotherapeutics in many cancers, including hepatocellular carcinoma (HCC). However, they are associated with problems such as low sensitivity to chemotherapy and the induction of liver injury, underscoring the need to identify new therapies. Here, we investigated the differential regulatory effect of metabotropic glutamate receptor 5 (mGlu5) on chemosensitivity in HCC and chemotoxicity to the normal liver. The expression of mGlu5 was higher in HCC than in the normal liver, and correlated with poor prognosis according to The Cancer Genome Atlas database and Integrative Molecular Database of Hepatocellular Carcinoma. Cisplatin, oxaliplatin or methyl methanesulfonate (MMS) caused cell death by decreasing mGlu5 expression in HCC cells and increased mGlu5 expression in hepatic cells. In HCC cells, inhibition of mGlu5 aggravated MMS-induced DNA damage by increasing intracellular Ca2+ overload and mitogen-activated protein kinase (MAPK) activation, thereby promoting cell death, and activation of mGlu5 rescued the effect of MMS. However, in hepatic cells, mGlu5 inhibition alleviated MMS-induced DNA damage by downregulating Ca2+-derived MAPK pathways to advance hepatic cell survival. The opposite effects of mGlu5 overexpression or knockdown on MMS-induced DNA damage supported that cell death is a result of the differential regulation of mGlu5 expression. Inhibition of mGlu5 increased chemosensitivity and decreased chemotoxicity in a rat tumor model. This study suggests that mGlu5 inhibition could act synergistically with HCC chemotherapeutics with minimal side effects, which may improve the treatment of patients with HCC in the future.