title: Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma.
abstract: 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.
authors.affiliation: University of Vermont, College of Medicine, Department of Pathology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: Cunniff
authors.affiliation: University of Pennsylvania School of Medicine, Division of Pulmonary, Thoracic Oncology Research Laboratory, Philadelphia, PA, 19147, United States of America.
authors.forename: Kheng
authors.initials: K
authors.lastname: Newick
authors.affiliation: Wake Forest School of Medicine, Department of Biochemistry, Medical Center Boulevard, Winston-Salem, NC, 27157, United States of America.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Nelson
authors.affiliation: University of Vermont, College of Medicine, Department of Pathology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America.
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Wozniak
authors.affiliation: University of Vermont, College of Medicine, Department of Pathology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America.
authors.forename: Stacie
authors.initials: S
authors.lastname: Beuschel
authors.affiliation: University of Vermont, College of Medicine, Department of Surgery, 149 Beaumont Ave, Burlington, VT, 05405, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Leavitt
authors.affiliation: University of Vermont, College of Medicine, Department of Radiology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America.
authors.forename: Anant
authors.initials: A
authors.lastname: Bhave
authors.affiliation: University of Vermont, College of Medicine, Department of Pathology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America.
authors.forename: Kelly
authors.initials: K
authors.lastname: Butnor
authors.affiliation: University of Vermont, Department of Immunology medicine, 149 Beaumont Ave, Burlington, VT, 05405, United States of America.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koenig
authors.affiliation: Medical Research Council, Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, United Kingdom; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, United Kingdom.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Chouchani
authors.affiliation: Medical Research Council, Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: James
authors.affiliation: Wake Forest School of Medicine, Department of Biochemistry, Medical Center Boulevard, Winston-Salem, NC, 27157, United States of America.
authors.forename: Alexina C
authors.initials: AC
authors.lastname: Haynes
authors.affiliation: Wake Forest School of Medicine, Department of Biochemistry, Medical Center Boulevard, Winston-Salem, NC, 27157, United States of America.
authors.forename: W Todd
authors.initials: WT
authors.lastname: Lowther
authors.affiliation: Medical Research Council, Mitochondrial Biology Unit, Hills Road, Cambridge, CB2 0XY, United Kingdom.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: University of Vermont, College of Medicine, Department of Pathology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America.
authors.forename: Arti
authors.initials: A
authors.lastname: Shukla
authors.affiliation: University of Vermont, College of Medicine, Department of Pathology, 149 Beaumont Ave, Burlington, VT, 05405, United States of America.
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Heintz
mesh_terms: D000818:Animals; D002374:Catalase / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism*; D000086002:Mesothelioma, Malignant; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010545:Peroxides / Q000378:metabolism*; D061105:Peroxiredoxin III / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013879:Thioredoxins / Q000378:metabolism; D013883:Thiostrepton / Q000494:pharmacology*
chemical_list: D010545:Peroxides; D013879:Thioredoxins; D061105:Peroxiredoxin III; D002374:Catalase; D013883:Thiostrepton