Hellfritsch Juliane, Kirsch Julian, Schneider Manuela, Fluege Tamara, Wortmann Markus, Frijhoff Jeroen, Dagnell Markus, Fey Theres, Esposito Irene, Kölle Pirkko, Pogoda Kristin, Angeli José Pedro Friedmann, Ingold Irina, Kuhlencordt Peter, Östman Arne, Pohl Ulrich, Conrad Marcus, Beck Heike
1 Walter Brendel Centre of Experimental Medicine, Munich Heart Alliance, Ludwig-Maximilians-University , Munich, Germany .
Antioxid Redox Signal. 2015 Apr 10;22(11):938-50. doi: 10.1089/ars.2014.5889.
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-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.
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.
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.
线粒体硫氧还蛋白还原酶（Txnrd2）通过作为硫氧还蛋白-过氧化物酶轴的直接电子供体，在控制线粒体过氧化氢（H2O2）丰度方面发挥核心作用。在本研究中，我们研究了靶向破坏Txnrd2对肿瘤生长的影响。
缺乏Txnrd2的肿瘤细胞无法激活缺氧诱导因子-1α（Hif-1α）信号；相反，它导致PHD2积累、Hif-1α降解以及血管内皮生长因子（VEGF）水平降低，最终导致肿瘤生长和肿瘤血管生成减少。c-Jun氨基末端激酶（JNK）激活增加被证明是Txnrd2缺失、线粒体氧化还原平衡改变以及谷氧还蛋白-2代偿性上调与PHD2表达升高之间的分子联系。
我们的数据为一种尚未被认识的线粒体Txnrd驱动的调节机制提供了有力证据，该机制最终可防止细胞内Hif-1α积累。此外，同时靶向线粒体硫氧还蛋白和谷胱甘肽系统被用作一种有效的治疗方法来阻碍肿瘤生长。
这项工作证明了线粒体Txnrd与JNK-PHD2-Hif-1α轴之间存在意想不到的调节联系，这突出了Txnrd2的缺失以及由此导致的线粒体氧化还原平衡改变如何损害肿瘤生长以及肿瘤相关血管生成。此外，它为通过同时靶向线粒体硫氧还蛋白和谷胱甘肽系统来阻碍肿瘤生长的治疗方法开辟了一条新途径。
