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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)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Inducible Factor 1-alpha; Smooth-muscle-cells; Hif-alpha; Peroxiredoxin-iii; Signaling Pathway; Factor Expression; Oxidative Stress; Complex-iii; Factor-i; Kappa-b
Sprache
Veröffentlichungsjahr 2015
HGF-Berichtsjahr 2015
ISSN (print) / ISBN 1523-0864
e-ISSN 1557-7716
Zeitschrift Antioxidants & Redox Signaling
Quellenangaben Band: 22, Heft: 11, Seiten: 938-950 Artikelnummer: , Supplement: ,
Verlag Mary Ann Liebert
Verlagsort New Rochelle
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)
Institute of Pathology (PATH)
Institute of Clinical Molecular Biology and Tumor Genetics (K.MOLBI)
POF Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
30204 - Cell Programming and Repair
Forschungsfeld(er) Genetics and Epidemiology
Enabling and Novel Technologies
Immune Response and Infection
PSP-Element(e) G-500500-004
G-500300-001
G-501400-001
G-500500-001
PubMed ID 25647640
DOI 10.1089/ars.2014.5889
WOS ID WOS:000351944100004
Scopus ID 84926322394
Erfassungsdatum 2015-04-05
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