title: Knockout of mitochondrial thioredoxin reductase stabilizes prolyl hydroxylase 2 and inhibits tumor growth and tumor-derived angiogenesis.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  Tumor cells with a Txnrd2 deficiency failed to activate hypoxia-inducible factor-1α (Hif-1α) signaling; it rather caused PHD2 accumulation, Hif-1α 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  This 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.
authors: 1 Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Ludwig-Maximilians-University , Munich, Germany .
authors: Juliane
authors: J
authors: Hellfritsch
authors: Julian
authors: J
authors: Kirsch
authors: Manuela
authors: M
authors: Schneider
authors: Tamara
authors: T
authors: Fluege
authors: Markus
authors: M
authors: Wortmann
authors: Jeroen
authors: J
authors: Frijhoff
authors: Markus
authors: M
authors: Dagnell
authors: Theres
authors: T
authors: Fey
authors: Irene
authors: I
authors: Esposito
authors: Pirkko
authors: P
authors: Kölle
authors: Kristin
authors: K
authors: Pogoda
authors: José Pedro Friedmann
authors: JP
authors: Angeli
authors: Irina
authors: I
authors: Ingold
authors: Peter
authors: P
authors: Kuhlencordt
authors: Arne
authors: A
authors: Östman
authors: Ulrich
authors: U
authors: Pohl
authors: Marcus
authors: M
authors: Conrad
authors: Heike
authors: H
authors: Beck
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D064593:Heterografts; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000235:genetics*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D054482:Thioredoxin Reductase 2; C516128:Txnrd2 protein, mouse
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