Repurposing disulfiram to induce OSCC cell death by cristae dysfunction promoted autophagy
Zhen Wang1, Han Jiang1, Lu-Yao Cai1
1State 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.
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.
Insights
Disulfiram suppresses oral squamous cell carcinoma by disrupting mitochondrial energy production, leading to excessive autophagy and cell death. Targeting OPA1-dependent ATP generation offers a new therapeutic strategy for oral cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Disulfiram (DSF) shows potential for cancer treatment but its mechanisms in oral squamous cell carcinoma (OSCC) are not fully understood.
- Investigating novel therapeutic strategies is crucial for improving OSCC patient outcomes.
Purpose of the Study:
- To evaluate the anti-cancer effects of disulfiram in oral squamous cell carcinoma.
- To elucidate the molecular mechanisms underlying disulfiram's anti-tumor activity in OSCC.
Main Methods:
- Cytotoxicity assays were performed using 3D culture and patient-derived xenograft (PDX) models of OSCC.
- Analysis included cell proliferation, apoptosis, signaling pathways, mitochondrial respiration, and mitochondrial mass.
- Mitochondrial DNA copy number and mitochondrial complex activities were assessed.
Main Results:
- Disulfiram induced excessive autophagy in OSCC cells by impairing oxidative phosphorylation (OXPHOS).
- DSF treatment led to OPA1 degradation, reducing mitochondrial respiration and ATP production.
- Energy depletion activated AMPK, resulting in excessive autophagy and cell death, which was rescued by exogenous ATP.
Conclusions:
- Disulfiram targets the mitochondrial inner membrane protein OPA1, disrupting cellular energy supply and inducing autophagy and cell death in OSCC.
- OPA1-dependent ATP generation is a potential therapeutic target for oral squamous cell carcinoma treatment.
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