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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Knockout of mitochondrial thioredoxin reductase stabilizes prolyl hydroxylase 2 and inhibits tumor growth and tumor-derived angiogenesis.
Antioxid. Redox Signal. 22, 938-950 (2015)
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
ISSN (print) / ISBN
1523-0864
e-ISSN
1557-7716
Zeitschrift
Antioxidants & Redox Signaling
Quellenangaben
Band: 22,
Heft: 11,
Seiten: 938-950
Verlag
Mary Ann Liebert
Verlagsort
New Rochelle
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed