Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective...

Area of Science:

• Biochemistry
• Cell Biology
• Oncology

Background:

• Cancer cells exhibit dysregulated metabolism, increasing mitochondrial hydrogen peroxide production, which fuels tumorigenesis.
• Solid tumors often up-regulate the mitochondrial thioredoxin reductase 2 (TRX2)--thioredoxin 2 (TXN2)--peroxiredoxin 3 (PRX3) antioxidant system to mitigate oxidative stress.

Purpose of the Study:

• To investigate the efficacy of thiostrepton (TS) and gentian violet (GV) in targeting the PRX3 antioxidant network in malignant mesothelioma cells.
• To evaluate the combined therapeutic effect of TS and GV on mesothelioma tumor growth in vivo.

Main Methods:

• Utilized malignant mesothelioma cells to demonstrate TS irreversibly disables PRX3 by crosslinking cysteine residues.
• Showed that GV targeting TRX2 potentiates PRX3 adduction by increasing disulfide-bonded PRX3 dimers.
• Assessed the impact of PRX3 knockdown on mesothelioma cell proliferation and sensitivity to TS.
• Evaluated the efficacy of combined TS and GV treatment in a SCID mouse xenograft model.

Main Results:

• TS irreversibly inhibits PRX3, while GV enhances this effect by increasing disulfide-bonded PRX3 dimers.
• Mesothelial cells with active PRX3 catalytic cycles are less sensitive to TS and GV.
• Stable knockdown of PRX3 reduces mesothelioma cell proliferation and increases sensitivity to TS.
• Combined TS and GV treatment significantly reduced tumor burden in a mesothelioma xenograft model compared to monotherapy.

Conclusions:

• Targeting the PRX3 antioxidant network with TS and GV represents a feasible redox-dependent strategy for mesothelioma treatment.
• This approach holds potential for managing other intractable human malignancies characterized by increased mitochondrial hydrogen peroxide production.