Mitochondrial thioredoxin reductase regulates major cytotoxicity pathways of proteasome inhibitors in multiple myeloma cells.
Mitochondrial thioredoxin reductase regulates major cytotoxicity pathways of proteasome inhibitors in multiple myeloma cells.
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DOI：
10.1038/leu.2015.190
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发表时间：
2016-01
期刊：
影响因子：
11.4
通讯作者：
Nikiforov MA
中科院分区：
文献类型：
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作者：
Fink EE;Mannava S;Bagati A;Bianchi-Smiraglia A;Nair JR;Moparthy K;Lipchick BC;Drokov M;Utley A;Ross J;Mendeleeva LP;Savchenko VG;Lee KP;Nikiforov MA
蛋白酶体抑制剂诱导的细胞内氧化应激是内质网应激的副产物。在这里，我们报告了一种机制，蛋白酶体抑制剂硼替佐米（BTZ）和卡非佐米（CFZ）的能力，直接诱导氧化和ER应激在多发性骨髓瘤（MM）细胞通过转录抑制基因编码的线粒体硫氧还蛋白还原酶（TXNRD2）。TXNRD2对维持细胞内氧化还原状态和活性氧的解毒至关重要。TXNRD2的耗竭到BTZ或CFZ处理的细胞中检测到的水平引起氧化应激、ER应激和死亡，类似于由蛋白酶体抑制剂诱导的那些。相反，与TXNRD2水平未恢复的细胞相比，用蛋白酶体抑制剂处理的MM细胞中近野生型TXNRD2量的恢复分别使氧化应激、ER应激和细胞死亡降低约46%、约35%和约50%。此外，从三个MM细胞系选择的耐BTZ的细胞表现出TXNRD 2的水平升高，间接证实其在BTZ耐药的功能作用。因此，免疫功能低下小鼠MM细胞异种移植物中TXNRD 2的异位表达减弱了BTZ的治疗作用。我们的数据确定TXNRD 2作为一个潜在的临床相关的目标，抑制蛋白酶体介导的细胞毒性，氧化应激和ER应激的关键。
It is generally accepted that intracellular oxidative stress induced by proteasome inhibitors is a byproduct of endoplasmic reticulum (ER) stress. Here, we report a mechanism underlying the ability of proteasome inhibitors bortezomib (BTZ) and carfilzomib (CFZ) to directly induce oxidative and ER stresses in multiple myeloma (MM) cells via transcriptional repression of a gene encoding mitochondrial thioredoxin reductase (TXNRD2). TXNRD2 is critical for maintenance of intracellular red-ox status and detoxification of reactive oxygen species. Depletion of TXNRD2 to the levels detected in BTZ- or CFZ-treated cells causes oxidative stress, ER stress and death similar to those induced by proteasome inhibitors. Reciprocally, restoration of near-wildtype TXNRD2 amounts in MM cells treated with proteasome inhibitors reduces oxidative stress, ER stress and cell death by ~46%, ~35% and ~50%, respectively, compared to cells with unrestored TXNRD2 levels. Moreover, cells from three MM cell lines selected for resistance to BTZ demonstrate elevated levels of TXNRD2, indirectly confirming its functional role in BTZ resistance. Accordingly, ectopic expression of TXNRD2 in MM cell xenografts in immunocompromised mice blunts therapeutic effects of BTZ. Our data identify TXNRD2 as a potentially clinically relevant target, inhibition of which is critical for proteasome inhibitor-dependent cytotoxicity, oxidative stress, and ER stress.