Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma

• Published in: PloS one Vol. 10; no. 5; p. e0127310
• Main Authors: Cunniff, Brian, Newick, Kheng, Nelson, Kimberly J, Wozniak, Alexandra N, Beuschel, Stacie, Leavitt, Bruce, Bhave, Anant, Butnor, Kelly, Koenig, Andreas, Chouchani, Edward T, James, Andrew M, Haynes, Alexina C, Lowther, W Todd, Murphy, Michael P, Shukla, Arti, Heintz, Nicholas H
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26-05-2015; Public Library of Science (PLoS)
• Subjects: Animals; Antioxidants; Apoptosis; Biochemistry; Biology; Cancer; Catalase; Catalase - metabolism; Catalysis; Cell cycle; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Combinatorial analysis; Councils; Crosslinking; Defects; Dimers; Drug therapy; Energy metabolism; Enzymes; Epithelium - drug effects; Epithelium - metabolism; Gene expression; Gentian violet; Health aspects; Humans; Hydrogen; Hydrogen ion concentration; Hydrogen peroxide; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Male; Medical research; Medicine; Mesothelioma; Mesothelioma - drug therapy; Mesothelioma - metabolism; Mesothelioma, Malignant; Metabolism; Mice; Mice, SCID; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Oxidation-Reduction - drug effects; Oxidoreductase; Pathology; Peroxides; Peroxides - metabolism; Peroxiredoxin; Peroxiredoxin III - metabolism; Physiological aspects; Prostate cancer; Proteins; Rats; Reductase; Sensitivity; Severe combined immunodeficiency; Signal Transduction - drug effects; Signal Transduction - physiology; Signaling; Solid tumors; Stress response; Thioredoxin; Thioredoxin 2; Thioredoxins; Thioredoxins - metabolism; Thiostrepton; Thiostrepton - pharmacology; Tumorigenesis; Xenografts; United States; United Kingdom
• DOI: 10.1371/journal.pone.0127310
• EISSN: 1932-6203

Dysregulation of signaling pathways and energy metabolism in cancer cells enhances production of mitochondrial hydrogen peroxide that supports tumorigenesis through multiple mechanisms. To counteract the adverse effects of mitochondrial peroxide many solid tumor types up-regulate the mitochondrial thioredoxin reductase 2--thioredoxin 2 (TRX2)--peroxiredoxin 3 (PRX3) antioxidant network. Using malignant mesothelioma cells as a model, we show that thiostrepton (TS) irreversibly disables PRX3 via covalent crosslinking of peroxidatic and resolving cysteine residues in homodimers, and that targeting the oxidoreductase TRX2 with the triphenylmethane gentian violet (GV) potentiates adduction by increasing levels of disulfide-bonded PRX3 dimers. Due to the fact that activity of the PRX3 catalytic cycle dictates the rate of adduction by TS, immortalized and primary human mesothelial cells are significantly less sensitive to both compounds. Moreover, stable knockdown of PRX3 reduces mesothelioma cell proliferation and sensitivity to TS. Expression of catalase in shPRX3 mesothelioma cells restores defects in cell proliferation but not sensitivity to TS. In a SCID mouse xenograft model of human mesothelioma, administration of TS and GV together reduced tumor burden more effectively than either agent alone. Because increased production of mitochondrial hydrogen peroxide is a common phenotype of malignant cells, and TS and GV are well tolerated in mammals, we propose that targeting PRX3 is a feasible redox-dependent strategy for managing mesothelioma and other intractable human malignancies.