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

Using malignant mesothelioma cells as a model, we show that thiostrepton irreversibly disables peroxiredoxin 3 via covalent crosslinking of peroxidatic and resolving cysteine residues in homodimers, and that targeting the oxidoreductase thioredoxin 2 with the triphenylmethane gentian violet potentiates adduction by increasing levels of disulfide-bonded PRX3 dimers

Brian Cunniff; Kheng Newick; Kimberly J. Nelson; Alexandra N. Wozniak; Stacie Beuschel; Bruce Leavitt; Anant Bhave; Kelly Butnor; Andreas Koenig; Edward T. Chouchani; Andrew M. James; Alexina C. Haynes; W. Todd Lowther; Michael P. Murphy; Arti Shukla; Nicholas H. Heintz

2015

Scholarcy highlights

  • Altered redox balance in tumor cells, characterized by an increase in the production of reactive oxygen species and changes in antioxidant gene expression, supports a pro-proliferative state and evasion from apoptosis
  • Evaluation of the effects of TS and gentian violet, alone or together, in a severe combined immunodeficient mouse xenograft model of human MM indicates combinatorial targeting of the peroxiredoxin 3 antioxidant network is a feasible strategy for managing a wide variety of tumors characterized by dysregulation of mitochondrial metabolism that results in high oxidant production
  • We investigated TS-induced modifications to recombinant PRX3 mutants where specific cysteine residues corresponding to cysteine at position 108, cysteine at position 229 and cysteine at position 127 were replaced with serine
  • Controlled and localized production of cellular hydrogen peroxide is required for growth factor signaling and cell cycle progression, and redox-responsive signaling pathways are known to be involved in cell differentiation, autophagy, migration and survival, all processes relevant to carcinogenesis
  • A pro-oxidant state is detrimental to normal cells, and oxidant levels are managed by a broad array of small molecules and a repertoire of antioxidant enzymes that include catalase, superoxide dismutase, glutathione peroxidases and peroxiredoxins
  • Given that it is a common feature of many tumor types, oxidant metabolism has emerged as an important therapeutic target, with accentuation of oxidant production that overwhelms antioxidant reserve capacity showing the most clinical promise
  • peroxiredoxin 3 was immunoprecipitated from 100 μg of total protein from control cell lysates and TS/gentian violet lysates and resolved by reducing and denaturing PAGE Bands corresponding to PRX3 monomers and dimers were recovered from the gel shown in panel C and digested with trypsin

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