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

TitleDisabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma.
Publication TypeJournal Article
Year of Publication2015
AuthorsCunniff, B, Newick, K, Nelson, KJ, Wozniak, AN, Beuschel, S, Leavitt, B, Bhave, A, Butnor, K, Koenig, A, Chouchani, ET, James, AM, Haynes, AC, W Lowther, T, Murphy, MP, Shukla, A, Heintz, NH
JournalPLoS One
Volume10
Issue5
Paginatione0127310
Date Published2015
ISSN1932-6203
KeywordsAnimals, Catalase, Cell Proliferation, Epithelium, Humans, Lung Neoplasms, Male, Mesothelioma, Mice, Mice, SCID, Mitochondria, Oxidation-Reduction, Peroxides, Peroxiredoxin III, Rats, Signal Transduction, Thioredoxins, Thiostrepton
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.

DOI10.1371/journal.pone.0127310
Alternate JournalPLoS ONE
Citation Key10.1371/journal.pone.0127310
PubMed ID26011724
PubMed Central IDPMC4444329
Grant ListGM050389 / GM / NIGMS NIH HHS / United States
GM072866 / GM / NIGMS NIH HHS / United States
P20GM103449 / GM / NIGMS NIH HHS / United States
P30 CA012197 / CA / NCI NIH HHS / United States
P30CA012197 / CA / NCI NIH HHS / United States
R01 ES021110 / ES / NIEHS NIH HHS / United States
T32 ES 007122 / ES / NIEHS NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada