Knockout of Mitochondrial Thioredoxin Reductase Stabilizes Prolyl Hydroxylase 2 and Inhibits Tumor Growth and Tumor-Derived Angiogenesis

Juliane Hellfritsch, Julian Kirsch, Manuela Schneider, Tamara Fluege, Markus Wortmann, Jeroen Frijhoff, Markus Dagnell, Theres Fey, Irene Esposito, Pirkko Koelle, Kristin Pogoda, Jose Pedro Friedmann Angeli, Irina Ingold, Peter Kuhlencordt, Arne Ostman, Ulrich Pohl, Marcus Conrad, Heike Beck*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

34 Citations (Web of Science)

Abstract

Mitochondrial thioredoxin reductase (Txnrd2) is a central player in the control of mitochondrial hydrogen peroxide (H2O2) abundance by serving as a direct electron donor to the thioredoxin-peroxiredoxin axis. In this study, we investigated the impact of targeted disruption of Txnrd2 on tumor growth.Tumor cells with a Txnrd2 deficiency failed to activate hypoxia-inducible factor-1? (Hif-1?) signaling; it rather caused PHD2 accumulation, Hif-1? degradation and decreased vascular endothelial growth factor (VEGF) levels, ultimately leading to reduced tumor growth and tumor vascularization. Increased c-Jun NH2-terminal Kinase (JNK) activation proved to be the molecular link between the loss of Txnrd2, an altered mitochondrial redox balance with compensatory upregulation of glutaredoxin-2, and elevated PHD2 expression.Our data provide compelling evidence for a yet-unrecognized mitochondrial Txnrd-driven, regulatory mechanism that ultimately prevents cellular Hif-1? accumulation. In addition, simultaneous targeting of both the mitochondrial thioredoxin and glutathione systems was used as an efficient therapeutic approach in hindering tumor growth.This work demonstrates an unexpected regulatory link between mitochondrial Txnrd and the JNK-PHD2-Hif-1? axis, which highlights how the loss of Txnrd2 and the resulting altered mitochondrial redox balance impairs tumor growth as well as tumor-related angiogenesis. Furthermore, it opens a new avenue for a therapeutic approach to hinder tumor growth by the simultaneous targeting of both the mitochondrial thioredoxin and glutathione systems.
Original languageEnglish
Pages (from-to)938-950
JournalAntioxidants & Redox Signaling
Volume22
Issue number11
DOIs
Publication statusPublished - 10 Apr 2015

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