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Identification of ANXA2 (annexin A2) as a specific bleomycin target to induce pulmonary fibrosis by impeding TFEB-mediated autophagic flux.

Authors
  • Wang, Kui1
  • Zhang, Tao2
  • Lei, Yunlong3
  • Li, Xuefeng4, 5
  • Jiang, Jingwen4
  • Lan, Jiang4
  • Liu, Yuan4
  • Chen, Haining6
  • Gao, Wei4
  • Xie, Na4
  • Chen, Qiang4
  • Zhu, Xiaofeng7
  • Liu, Xiang8
  • Xie, Ke9
  • Peng, Yong4
  • Nice, Edouard C10
  • Wu, Min5
  • Huang, Canhua1
  • Wei, Yuquan4
  • 1 a State Key Laboratory of Biotherapy and Cancer Center , West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China. , (China)
  • 2 b The School of Biomedical Sciences , Chengdu Medical College , Chengdu , China. , (China)
  • 3 c Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center , Chongqing Medical University , Chongqing , China. , (China)
  • 4 d State Key Laboratory of Biotherapy and Cancer Center , West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu , China. , (China)
  • 5 e Department of Biomedical Sciences , University of North Dakota , Grand Forks , ND , USA.
  • 6 f Department of Gastrointestinal Surgery , West China Hospital, Sichuan University , Chengdu , China. , (China)
  • 7 g College of Life Science , Sichuan University , Chengdu , China. , (China)
  • 8 h Department of Pathology , Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital , Chengdu , China. , (China)
  • 9 i Department of Oncology , Sichuan Provincial People's Hospital , Chengdu , China. , (China)
  • 10 j Department of Biochemistry and Molecular Biology , Monash University , Clayton , Victoria , Australia. , (Australia)
Type
Published Article
Journal
Autophagy
Publisher
Landes Bioscience
Publication Date
Jan 29, 2018
Pages
1–14
Identifiers
DOI: 10.1080/15548627.2017.1409405
PMID: 29172997
Source
Medline
Keywords
License
Unknown

Abstract

Bleomycin is a clinically potent anticancer drug used for the treatment of germ-cell tumors, lymphomas and squamous-cell carcinomas. Unfortunately, the therapeutic efficacy of bleomycin is severely hampered by the development of pulmonary fibrosis. However, the mechanisms underlying bleomycin-induced pulmonary fibrosis, particularly the molecular target of bleomycin, remains unknown. Here, using a chemical proteomics approach, we identify ANXA2 (annexin A2) as a direct binding target of bleomycin. The interaction of bleomycin with ANXA2 was corroborated both in vitro and in vivo. Genetic depletion of anxa2 in mice mitigates bleomycin-induced pulmonary fibrosis. We further demonstrate that Glu139 (E139) of ANXA2 is required for bleomycin binding in lung epithelial cells. A CRISPR-Cas9-engineered ANXA2E139A mutation in lung epithelial cells ablates bleomycin binding and activates TFEB (transcription factor EB), a master regulator of macroautophagy/autophagy, resulting in substantial acceleration of autophagic flux. Pharmacological activation of TFEB elevates bleomycin-initiated autophagic flux, inhibits apoptosis and proliferation of epithelial cells, and ameliorates pulmonary fibrosis in bleomycin-treated mice. Notably, we observe lowered TFEB and LC3B levels in human pulmonary fibrosis tissues compared to normal controls, suggesting a critical role of TFEB-mediated autophagy in pulmonary fibrosis. Collectively, our data demonstrate that ANXA2 is a specific bleomycin target, and bleomycin binding with ANXA2 impedes TFEB-induced autophagic flux, leading to induction of pulmonary fibrosis. Our findings provide insight into the mechanisms of bleomycin-induced fibrosis and may facilitate development of optimized bleomycin therapeutics devoid of lung toxicity.

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