Adeno-associated virus-delivered alpha synuclein inhibits bladder cancer growth via the p53/p21 signaling pathway

• Published in: Cancer gene therapy 2022-08, Vol.29 (8-9), p.1193-1206
• Main Authors: Wu, Zhengcun, Xia, Chengxing, Zhang, Chao, Tang, Donghong, Liu, Feineng, Ou, Yitian, Gao, Jiahong, Yi, Hongkun, Yang, Delin, Ma, Kaili
• Format: Article
• Language: English
• Subjects: 13/44; 45/23; 45/47; 45/77; 59/5; 631/67/589/1336; 631/80; 64/60; 692/699/67/589/1336; 96/34; 96/95; Apoptosis; Biomedical and Life Sciences; Biomedicine; Bladder cancer; Cancer; Cell cycle; Cell proliferation; Cyclin-dependent kinase inhibitor p21; Gene Expression; Gene Therapy; Homeostasis; Kinases; Malignancy; Mitochondria; Movement disorders; Neurodegenerative diseases; Oxidative stress; p53 Protein; Parkinson's disease; Pathophysiology; S phase; Signal transduction; Synuclein; Therapeutic targets; Tumor suppressor genes; Tumors
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/s41417-022-00425-w

Alpha-synuclein (α-syn), encoded by the SNCA gene, is a major participant in the pathophysiology of Parkinson’s disease (PD). Its functions have been reported to be related to apoptosis induction, the elevation of oxidative stress, mitochondrial homeostasis, cell-cycle aberrations, and DNA-related interactions. Evidence obtained in recent studies suggests a possible link between α-syn and cancer development. Bladder cancer (BCa) is the second most common genitourinary malignancy, with the population of survivors of BCa increasing worldwide. In this study, we show that α-syn expression was significantly downregulated in BCa. In vitro and in vivo experiments showed that α-syn could significantly inhibit BCa cell proliferation by arresting the cell cycle in the S phase via upregulation of p53 expression mediated by DNA damages. Further experiments showed that overexpression of α-syn delivered by adeno-associated viruses (AAVs) exerted inhibitory effects on the growth of BCa tumors. These findings indicate that αα-syn is a functional tumor suppressor that can inhibit the proliferation of BCa cells by activating the p53/p21 signaling pathway. Our present study provides insights into the roles of α-syn in BCa and suggests that α-syn may be a novel therapeutic target for the treatment of BCa.