Cited by 15Autophagy in Disease and TherapyMitochondrial Function and PathologyCell death mechanisms and regulation

Repurposing disulfiram to induce OSCC cell death by cristae dysfunction promoted autophagy

Wang, Zhen, Jiang, Han, Cai, Lu‐Yao, Ji, Ning, Zeng, Xin, Zhou, Yu, Shen, Ying‐Qiang, Chen, Qian‐Ming·2021·Oral Diseases

Abstract

Objective: Disulfiram has been repurposed as a potential candidate to suppress various cancers. However, its anti‐tumor effects and molecular mechanisms of oral squamous cell carcinoma remain unclear. In this study, we aimed to assess the anti‐cancer activity and underlying mechanisms of disulfiram in the context of oral squamous cell carcinoma. Materials and Methods: We tested the cytotoxicity of disulfiram in oral squamous cell carcinoma using a 3D culture model and a PDX model. Cell proliferation, cell death, and related signaling pathways were evaluated. Mitochondrial DNA copy number, mitochondrial respiration, mitochondrial mass, and mitochondrial complexes were analyzed. Results: Disulfiram can induce excessive autophagy in oral squamous cell carcinoma cells as a result of OXPHOS deficiency. Disulfiram‐induced OPA1 degradation can impair the functional cristae structure, which results in a dramatic reduction in mitochondrial respiration capability as well as ATP production. Subsequently, energy deprivation leads to excessive autophagy through AMPK activation. In addition, exogenous ATP blocked the activation of AMPK and rescued disulfiram‐induced cell death. Conclusion: DSF targets mitochondrial inner membrane protein OPA1 to disturb the energy supply, triggering excessive autophagy, and cell death in OSCC. Our study suggests OPA1‐dependent ATP generation is pharmacologically targetable in OSCC treatment.

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Crossref · 10.1111/odi.13652

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  • Disulfiram triggers excessive autophagy via oxidative phosphorylation (OXPHOS) deficiency; OPA1 degradation disrupts cristae structure, reducing mitochondrial respiration and ATP production, and energy deprivation activates AMPK, driving autophagy.

    “The drug triggers excessive autophagy via oxidative phosphorylation (OXPHOS) deficiency. Specifically, optic atrophy protein 1 (OPA1) degradation disrupts cristae structure, sharply reducing mitochondrial respiration and ATP production. This energy deprivation activates adenosine monophosphate-activated protein kinase (AMPK), driving autophagy.76”

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Authors
Wang, Z., Jiang, H., Cai, L., Ji, N., Zeng, X., Zhou, Y., Shen, Y., & Chen, Q.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • State Key Laboratory of Oral Diseases National Clinical Research Center for Oral Diseases Chinese Academy of Medical Sciences Research Unit of Oral Medicine of Carcinogenesis and Management West China Hospital of Stomatology Sichuan University Chengdu China
Corresponding author
Zhou, Yu
Venue
Oral Diseases
Publisher
Wiley
Published
2020-10-14
Volume
27
Issue
5
Pages
1148-1160
ISSN
  • 1354-523X (ISSN-L)
  • 1601-0825
OpenAlex
W3089521919
Cited by
15
References
40
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 3
FWCI
0.90
Type
journal article
Language
en
Open access
closed
Locations
  • Oral Diseases (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81520108009, 81902784)
  • China Postdoctoral Science Foundation (2019M650247)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
disulfiram, oral squamous cell carcinoma, drug repurposing, autophagy, mitochondrial respiration, AMPK activation, ATP depletion, cell death, mitochondrial DNA copy number, xenograft models
MeSH terms
Autophagy, Carcinoma, Squamous Cell, Disulfiram, Head and Neck Neoplasms, Humans, Mouth Neoplasms, Cell Death, Apoptosis, Cell Line, Tumor, Cell Proliferation

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