2. Academic Validation
  3. Nitazoxanide impairs mitophagy flux through ROS-mediated mitophagy initiation and lysosomal dysfunction in bladder cancer

Nitazoxanide impairs mitophagy flux through ROS-mediated mitophagy initiation and lysosomal dysfunction in bladder cancer

  • Biochem Pharmacol. 2021 Aug;190:114588. doi: 10.1016/j.bcp.2021.114588.
Haiyan Sun 1,  Tong Ou 2,  Jianyang Hu 3,  Ziyi Yang 1,  Qifang Lei 1,  Yuqing Li 1,  Gang Wang 1,  Yongpeng Li 1,  Kai Wu 1,  Shupeng Wang 1,  Song Wu 4
Affiliations

Affiliations

  • 1 Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China; Shenzhen Following Precision Medical Research Institute, Luohu Hospital Group, Shenzhen 518000, China.
  • 2 Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China; Shenzhen Following Precision Medical Research Institute, Luohu Hospital Group, Shenzhen 518000, China; Medical Laboratory, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China.
  • 3 Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China.
  • 4 Institute of Urology, The Third Affiliated Hospital of Shenzhen University (Luohu Hospital Group), Shenzhen 518000, China; Shenzhen Following Precision Medical Research Institute, Luohu Hospital Group, Shenzhen 518000, China; Teaching Center of Shenzhen Luohu Hospital, Shantou University Medical College, Shenzhen 518000, China; Department of Urology and Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China. Electronic address: wusong@szu.edu.cn.
PMID: 33957094 DOI: 10.1016/j.bcp.2021.114588
Abstract

Bladder Cancer is one of the most common malignancy in the urinary tract with high recurrence and drug resistance in clinics. Alternative treatments from existing drugs might be a promising strategy. Nitazoxanide (NTZ), an FDA-approved antiprotozoal drug, has got increasingly noticed because of its favorable safety profile and antitumor potential, yet the effects in bladder Cancer and underlying mechanisms remain poorly understood. Herein, we find that NTZ induces mitochondrial damage and Mitophagy initiation through PINK1-generated phospho-ubiquitin(pS65-Ub) and Autophagy receptor-mediated pathway even in the absence of Atg5/Beclin1. Meanwhile, NTZ inhibits lysosomal degradation activity, leading to Mitophagy flux impairment at late stage. Mitochondrial Reactive Oxygen Species (ROS) production is critical in this process, as eliminating ROS with N-acetylcysteine (NAC) efficiently inhibits PINK1 signaling-mediated Mitophagy initiation and alleviates lysosomal dysfunction. Co-treatment with NTZ and Autophagy Inhibitor Chloroquine (CQ) to aggravate Mitophagy flux impairment promotes NTZ-induced Apoptosis, while alleviation of Mitophagy flux impairment with ROS scavenger reduces cell death. Moreover, we also discover a similar signaling response in the 3D bladder tumor spheroid after NTZ exposure. In vivo study reveals a significant inhibition of orthotopic bladder tumors with no obvious systemic toxicity. Together, our results uncover the anti-tumor activities of NTZ with the involvement of ROS-mediated Mitophagy modulation at different stages and demonstrate it as a potential drug candidate for fighting against bladder tumors.

Keywords

Lysosomal dysfunction; Mitophagy flux impairment; Mitophagy initiation; Nitazoxanide; PINK1; Reactive oxygen species.

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