Knockout of Mitochondrial Thioredoxin Reductase Stabilizes Prolyl Hydroxylase 2 and Inhibits Tumor Growth and Tumor-Derived Angiogenesis
Knockout of Mitochondrial Thioredoxin Reductase Stabilizes Prolyl Hydroxylase 2 and Inhibits Tumor Growth and Tumor-Derived Angiogenesis
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DOI：
10.1089/ars.2014.5889
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发表时间：
2015-04-10
影响因子：
6.6
通讯作者：
Beck, Heike
中科院分区：
文献类型：
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作者：
Hellfritsch, Juliane;Kirsch, Julian;Beck, Heike
目的：线粒体硫氧还蛋白还原酶 (Txnrd2) 作为硫氧还蛋白-过氧化氧还蛋白轴的直接电子供体，是控制线粒体过氧化氢 (H2O2) 丰度的核心角色。在这项研究中，我们研究了 Txnrd2 的靶向破坏对肿瘤生长的影响。结果：Txnrd2 缺陷的肿瘤细胞无法激活缺氧诱导因子 1 α (Hif-1 α) 信号传导；相反，它会导致 PHD2 积累、Hif-1 α 降解和血管内皮生长因子 (VEGF) 水平降低，最终导致肿瘤生长和肿瘤血管化减少。 c-Jun NH2 末端激酶 (JNK) 激活的增加被证明是 Txnrd2 缺失、线粒体氧化还原平衡改变与谷氧还蛋白 2 代偿性上调和 PHD2 表达升高之间的分子联系。创新：我们的数据为尚未认识的线粒体 Txnrd 驱动的调节机制提供了令人信服的证据，该机制最终阻止细胞 Hif-1 α 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阻碍肿瘤生长的有效治疗方法。结论：这项工作证明了线粒体 Txnrd 和 JNK-PHD2-Hif-1 α 轴之间存在意想不到的调节联系，这凸显了 Txnrd2 的缺失以及由此产生的线粒体氧化还原平衡的改变如何损害肿瘤生长以及肿瘤相关的血管生成。此外，它还为通过同时靶向线粒体硫氧还蛋白和谷胱甘肽系统来抑制肿瘤生长的治疗方法开辟了新途径。抗氧化剂。氧化还原信号。 22、938-950。
Aims: 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-1 alpha (Hif-1 alpha) signaling; it rather caused PHD2 accumulation, Hif-1 alpha 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. Innovation: Our data provide compelling evidence for a yet-unrecognized mitochondrial Txnrd-driven, regulatory mechanism that ultimately prevents cellular Hif-1 alpha 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: This work demonstrates an unexpected regulatory link between mitochondrial Txnrd and the JNK-PHD2-Hif-1 alpha 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. Antioxid. Redox Signal. 22, 938-950.