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

Cancer Gene Therapy volume 29, pages 1193–1206 (2022)Cite this article

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Abstract

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.

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Fig. 1: SNCA expression is downregulated in BCa tissues.
Fig. 2: α-syn affects BCa cell proliferation in vitro.
Fig. 3: α-syn reduces tumor growth in vivo.
Fig. 4: α-syn shows positive interactions with p53 in bladder cancer.
Fig. 5: Cell cycle in BCa cell lines is arrested in the S phase by α-syn via the p53/p21 pathway.
Fig. 6: α-syn induces DNA damage in BCa cells.
Fig. 7: Growth of BCa tumors is significantly suppressed by α-syn delivered by AAVs via the p53/p21 signaling pathway.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81860453), Natural Science Foundation of Yunnan Province (Nos. 2018ZF009; 2018FE001 (-006); 202001AT070144), and CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-2-001).

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  1. These authors contributed equally: Zhengcun Wu, Chengxing Xia.

Authors and Affiliations

  1. Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 650118, Kunming, China

    Zhengcun Wu, Donghong Tang, Jiahong Gao, Hongkun Yi & Kaili Ma

  2. Department of Urology, The Second Affiliated Hospital of Kunming Medical University, 650101, Kunming, China

    Chengxing Xia, Feineng Liu, Yitian Ou & Delin Yang

  3. Oncology Department, The First People’s hospital of Qujing, 655000, Qujing, China

    Chao Zhang

  4. Medical Primate Research Center & Neuroscience Center, Chinese Academy of Medical Sciences, 100005, Beijing, China

    Kaili Ma

  5. Yunnan Key Laboratory of Vaccine Research Development on Severe Infectious Diseases, 650118, Kunming, China

    Kaili Ma

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KM and DY discussed and designed this study. ZW, CX, FL, YO, and JG performed all experiments. The manuscript was written by ZW and CX. CZ and DT revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Delin Yang or Kaili Ma.

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Wu, Z., Xia, C., Zhang, C. et al. Adeno-associated virus-delivered alpha synuclein inhibits bladder cancer growth via the p53/p21 signaling pathway. Cancer Gene Ther 29, 1193–1206 (2022). https://doi.org/10.1038/s41417-022-00425-w

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