The Parkinson's disease-associated protein α-synuclein inhibits hepatoma by exosome delivery
Tian-Zhong Hou
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorHui-Min Yang
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorYun-Zhong Cheng
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorLi Gu
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorJian-Nan Zhang
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorCorresponding Author
Hong Zhang
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Correspondence Hong Zhang, Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, People's Republic of China.
Email: [email protected]
Search for more papers by this authorTian-Zhong Hou
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorHui-Min Yang
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorYun-Zhong Cheng
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorLi Gu
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorJian-Nan Zhang
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Search for more papers by this authorCorresponding Author
Hong Zhang
Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, People's Republic of China
Correspondence Hong Zhang, Department of Neurobiology, School of Basic Medical Sciences, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, People's Republic of China.
Email: [email protected]
Search for more papers by this authorAbstract
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 αVβ5 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.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
REFERENCES
- 1Devine MJ, Plun-Favreau H, Wood NW. Parkinson's disease and cancer: two wars, one front. Nat Rev Cancer. 2011; 11(11): 813-823.
- 2Park JH, Kim DH, Park YG, et al. Cancer risk in patients with Parkinson's disease in South Korea: a nationwide, population-based cohort study. Eur J Cancer. 2019; 117: 5-13.
- 3Rugbjerg K, Friis S, Lassen CF, Ritz B, Olsen JH. Malignant melanoma, breast cancer and other cancers in patients with Parkinson's disease. Int J Cancer. 2012; 131(8): 1904-1911.
- 4Ong EL, Goldacre R, Goldacre M. Differential risks of cancer types in people with Parkinson's disease: a national record-linkage study. Eur J Cancer. 2014; 50(14): 2456-2462.
- 5Ajdacic-Gross V, Rodgers S, Aleksandrowicz A, et al. Cancer co-occurrence patterns in Parkinson's disease and multiple sclerosis—do they mirror immune system imbalances? Cancer Epidemiol. 2016; 44: 167-173.
- 6Bai XX, Gu L, Yang HM, et al. Downregulation of metabotropic glutamate receptor 5 inhibits hepatoma development in a neurotoxin rotenone-induced Parkinson's disease model. Toxicol Lett. 2018; 288: 71-81.
- 7Xi SS, Bai XX, Gu L, et al. Metabotropic glutamate receptor 5 mediates the suppressive effect of 6-OHDA-induced model of Parkinson's disease on liver cancer. Pharmacol Res. 2017; 121: 145-157.
- 8Balestrino R, Schapira AHV. Parkinson disease. Eur J Neurol. 2020; 27(1): 27-42.
- 9Junn E, Mouradian MM. Human α-synuclein over-expression increases intracellular reactive oxygen species levels and susceptibility to dopamine. Neurosci Lett. 2002; 320(3): 146-150.
- 10Chen L, Feany MB. α-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nature Neurosci. 2005; 8(5): 657-663.
- 11Zhang X, Wu Z, Ma K. SNCA correlates with immune infiltration and serves as a prognostic biomarker in lung adenocarcinoma. BMC Cancer. 2022; 22(1): 406.
- 12Vareed SK, Bhat VB, Thompson C, et al. Metabolites of purine nucleoside phosphorylase (NP) in serum have the potential to delineate pancreatic adenocarcinoma. PLoS One. 2011; 6(3):e17177.
- 13Li W, Zhang H, Guo Q, et al. Detection of SNCA and FBN1 methylation in the stool as a biomarker for colorectal cancer. Dis Markers. 2015; 2015: 1-6.
- 14Wu Z, Xia C, Zhang C, Yang D, Ma K. Prognostic significance of SNCA and its methylation in bladder cancer. BMC Cancer. 2022; 22(1): 330.
- 15Lee BR, Matsuo Y, Cashikar AG, Kamitani T. Role of Ser129 phosphorylation of α-synuclein in melanoma cells. J Cell Sci. 2013; 126(Pt 2): 696-704.
- 16Zhang S, Eitan E, Wu TY, Mattson MP. Intercellular transfer of pathogenic α-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal. Neurobiol Aging. 2018; 61: 52-65.
- 17Danzer KM, Kranich LR, Ruf WP, et al. Exosomal cell-to-cell transmission of alpha-synuclein oligomers. Mol Neurodegener. 2012; 7: 42.
- 18Shi M, Liu C, Cook TJ, et al. Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuropathol. 2014; 128(5): 639-650.
- 19Costa-Silva B, Aiello NM, Ocean AJ, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nature Cell Biol. 2015; 17(6): 816-826.
- 20Fang T, Lv H, Lv G, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018; 9(1): 191.
- 21Zuo B, Qi H, Lu Z, et al. Alarmin-painted exosomes elicit persistent antitumor immunity in large established tumors in mice. Nat Commun. 2020; 11(1): 1790.
- 22Hannafon B, Ding WQ. Intercellular communication by exosome-derived microRNAs in cancer. Int J Mol Sci. 2013; 14(7): 14240-14269.
- 23Wu Q, Zhou L, Lv D, Zhu X, Tang H. Exosome-mediated communication in the tumor microenvironment contributes to hepatocellular carcinoma development and progression. J Hematol Oncol. 2019; 12(1): 53.
- 24Levi M, DeRemer SJ, Dou C, Ensminger WD, Smith DE. Disposition of WR-1065 in the liver of tumor-bearing rats following regional vs systemic administration of amifostine. Biopharm Drug Dispos. 2004; 25(1): 27-35.
- 25Radad K, Al-Shraim M, Al-Emam A, et al. Rotenone: from modelling to implication in Parkinson's disease. Folia Neuropathol. 2019; 57(4): 317-326.
- 26Wang G, Zhao X, Li DC. Expression of HIP/PAP in hepatocellular carcinoma and effect of siRNA on migration and invasion in HCC cells. Asian Pac J Trop Med. 2015; 8(10): 848-854.
- 27Bai H, Weng Y, Bai S, et al. CCL5 secreted from bone marrow stromal cells stimulates the migration and invasion of Huh7 hepatocellular carcinoma cells via the PI3K-Akt pathway. Int J Oncol. 2014; 45(1): 333-343.
- 28Wu F, Xu HD, Guan JJ, et al. Rotenone impairs autophagic flux and lysosomal functions in Parkinson's disease. Neuroscience. 2015; 284: 900-911.
- 29Alvarez-Erviti L, Seow Y, Schapira AH, et al. Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol Dis. 2011; 42(3): 360-367.
- 30Hoshino A, Costa-Silva B, Shen TL, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015; 527(7578): 329-335.
- 31Delenclos M, Trendafilova T, Mahesh D, et al. Investigation of endocytic pathways for the internalization of exosome-associated oligomeric alpha-synuclein. Front Neurosci. 2017; 11: 172.
- 32Stuendl A, Kraus T, Chatterjee M, et al. α-synucleinin plasma-derived extracellular vesicles is a potential biomarker of Parkinson's disease. Mov Disorders. 2021; 36(11): 2508-2518.
- 33Cerri S, Mus L, Blandini F. Parkinson's disease in women and men: what's the difference? J Parkinson's Dis. 2019; 9(3): 501-515.
- 34Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018; 68(6): 394-424.
- 35Chang CW, Yang SY, Yang CC, Chang CW, Wu YR. Plasma and serum alpha-synuclein as a biomarker of diagnosis in patients with Parkinson's disease. Front Neurol. 2020; 10: 1388.
- 36Wang L, Wang G, Duan Y, et al. A comparative study of the diagnostic potential of plasma and erythrocytic α-synuclein in Parkinson's disease. Neurodegener Dis. 2019; 19(5-6): 204-210.
- 37Caswell PT, Norman JC. Integrin trafficking and the control of cell migration. Traffic. 2006; 7(1): 14-21.
- 38Yan Y, Xu Z, Hu X, et al. SNCA is a functionally low-expressed gene in lung adenocarcinoma. Genes. 2018; 9(1): 16.
- 39Dai J, Su Y, Zhong S, et al. Exosomes: key players in cancer and potential therapeutic strategy. Signal Transduct Target Ther. 2020; 5(1): 145.
- 40Overk CR, Cartier A, Shaked G, et al. Hippocampal neuronal cells that accumulate α-synuclein fragments are more vulnerable to Aβ oligomer toxicity via mGluR5—implications for dementia with Lewy bodies. Mol Neurodegener. 2014; 9: 18.
- 41Marengo A, Rosso C, Bugianesi E. Liver cancer: connections with obesity, fatty liver, and cirrhosis. Annu Rev Med. 2016; 67: 103-117.
