Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma.
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 t...
Main Authors: | , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2015-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4444329?pdf=render |
id |
doaj-80663c10267047e390e70d5eff6a490e |
---|---|
record_format |
Article |
spelling |
doaj-80663c10267047e390e70d5eff6a490e2020-11-24T20:49:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01105e012731010.1371/journal.pone.0127310Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma.Brian CunniffKheng NewickKimberly J NelsonAlexandra N WozniakStacie BeuschelBruce LeavittAnant BhaveKelly ButnorAndreas KoenigEdward T ChouchaniAndrew M JamesAlexina C HaynesW Todd LowtherMichael P MurphyArti ShuklaNicholas H HeintzDysregulation 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.http://europepmc.org/articles/PMC4444329?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. PLoS ONE |
author_facet |
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 |
author_sort |
Brian Cunniff |
title |
Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. |
title_short |
Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. |
title_full |
Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. |
title_fullStr |
Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. |
title_full_unstemmed |
Disabling Mitochondrial Peroxide Metabolism via Combinatorial Targeting of Peroxiredoxin 3 as an Effective Therapeutic Approach for Malignant Mesothelioma. |
title_sort |
disabling mitochondrial peroxide metabolism via combinatorial targeting of peroxiredoxin 3 as an effective therapeutic approach for malignant mesothelioma. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2015-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4444329?pdf=render |
work_keys_str_mv |
AT briancunniff disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT khengnewick disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT kimberlyjnelson disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT alexandranwozniak disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT staciebeuschel disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT bruceleavitt disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT anantbhave disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT kellybutnor disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT andreaskoenig disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT edwardtchouchani disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT andrewmjames disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT alexinachaynes disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT wtoddlowther disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT michaelpmurphy disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT artishukla disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma AT nicholashheintz disablingmitochondrialperoxidemetabolismviacombinatorialtargetingofperoxiredoxin3asaneffectivetherapeuticapproachformalignantmesothelioma |
_version_ |
1716805406500585472 |