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.