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Hellfritsch, J.* ; Kirsch, J.* ; Schneider, M.* ; Fluege, T. ; Wortmann, M.* ; Frijhoff, J.* ; Dagnell, M.* ; Fey, T.* ; Esposito, I. ; Kölle, P.* ; Pogoda, K.* ; Ingold, I.* ; Friedmann Angeli, J.P.F.* ; Kuhlencordt, P.* ; Östman, A.* ; Pohl, U.* ; Beck, H.* ; Conrad, M.

Knockout of mitochondrial thioredoxin reductase stabilizes prolyl hydroxylase 2 and inhibits tumor growth and tumor-derived angiogenesis.

Antioxid. Redox Signal. 22, 938-950 (2015)
Open Access Green as soon as Postprint is submitted to ZB.
Aims: Mitochondrial thioredoxin reductase (Txnrd2) is a central player in the control of mitochondrial H2O2 abundance by serving as a direct electron donor to the thioredoxin-peroxiredoxin axis. In the present study we investigated the impact of targeted disruption of Txnrd2 on tumor growth. Results: Tumor cells with a Txnrd2-deficiency failed to activate HIF-1α signaling; it rather caused PHD2 accumulation, HIF-1α degradation and decreased 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. Innovation: Our data provide compelling evidence for a yet unrecognized mitochondrial Txnrd-driven, regulatory mechanism that ultimately prevents cellular HIF-1α accumulation. In addition, simultaneous targeting of both the mitochondrial thioredoxin and glutathione systems was used as an efficient therapeutic approach in hindering tumor growth. Conclusion: The present work demonstrates an unexpected regulatory link between mitochondrial Txnrd and the JNK-PHD2-HIF-1α 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Inducible Factor 1-alpha; Smooth-muscle-cells; Hif-alpha; Peroxiredoxin-iii; Signaling Pathway; Factor Expression; Oxidative Stress; Complex-iii; Factor-i; Kappa-b
ISSN (print) / ISBN 1523-0864
e-ISSN 1557-7716
Quellenangaben Volume: 22, Issue: 11, Pages: 938-950 Article Number: , Supplement: ,
Publisher Mary Ann Liebert
Publishing Place New Rochelle
Reviewing status Peer reviewed