The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation
The thioredoxin reductase inhibitor auranofin triggers apoptosis through a Bax/Bak-dependent process that involves peroxiredoxin 3 oxidation
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DOI：
10.1016/j.bcp.2008.08.021
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发表时间：
2008-10-30
影响因子：
5.8
通讯作者：
Hampton, Mark B.
中科院分区：
文献类型：
--
作者：
Cox, Andrew G.;Brown, Kristin K.;Hampton, Mark B.
硫氧还蛋白还原酶（TrxR）是一种重要的硒蛋白抗氧化酶，是抗癌药物的潜在靶点。TrxR的一种有效抑制剂是金（1）化合物金诺芬，它可以触发细胞依赖性凋亡途径。金诺芬诱导细胞凋亡的确切机制尚不清楚，但有迹象表明线粒体氧化应激是一个中心事件。我们评估了氧化还原状态的过氧化物酶（Prxs）在Jurkat T淋巴瘤细胞与金诺芬处理，发现线粒体Prx 3是相当敏感的氧化比胞浆Prx 1和2，表明选择性线粒体应激。在几种细胞类型中，在金诺芬的凋亡剂量下检测到Prx 3氧化，并且在其他线粒体事件包括细胞色素c释放和线粒体去极化之前发生。金诺芬还能够使U937细胞对TNF-α介导的凋亡敏感。金诺芬诱导的细胞凋亡被Bcl-2的过表达有效地阻断，Bax/巴克缺陷小鼠胚胎成纤维细胞也对细胞凋亡具有抗性，表明该家族的促凋亡蛋白在金诺芬触发的细胞凋亡中起着核心作用。金诺芬暴露抑制了抗肿瘤细胞的增殖，并且在较高剂量的金诺芬下，可以通过坏死引起细胞死亡。我们的结论是，金诺芬诱导细胞凋亡，通过Bax/Bak-dependent机制与选择性破坏线粒体氧化还原稳态结合Prx 3的氧化。(C)2008年爱思唯尔公司All rights reserved.
Thioredoxin reductase (TrxR) is a key selenoprotein antioxidant enzyme and a potential target for anti-cancer drugs. One potent inhibitor of TrxR is the gold (1) compound auranofin, which can trigger mitochondrial-dependent apoptosis pathways. The exact mechanism of apoptosis induction by auranofin is not yet clear, but there are indications that mitochondrial oxidative stress is a central event. We assessed the redox state of the peroxiredoxins (Prxs) in Jurkat T-lymphoma cells treated with auranofin, and found that mitochondrial Prx3 was considerably more sensitive to oxidation than the cytosolic Prx1 and 2, indicating selective mitochondrial stress. Prx3 oxidation was detected at apoptotic doses of auranofin in several cell types, and occurred before other mitochondrial events including cytochrome c release and mitochondrial depolarisation. Auranofin was also able to sensitise U937 cells to TNF-alpha-mediated apoptosis. Auranofin-induced apoptosis was effectively blocked by the overexpression of Bcl-2, and Bax/Bak deficient mouse embryonic fibroblasts were also resistant to apoptosis, indicating a central role for the pro-apoptotic proteins of this family in auranofin-triggered apoptosis. Auranofin exposure inhibited the proliferation of apoptosis-resistant cells, and at higher doses of auranofin could cause cell death through necrosis. We conclude that auranofin induces apoptosis in cells through a Bax/Bak-dependent mechanism associated with selective disruption of mitochondrial redox homeostasis in conjunction with oxidation of Prx3. (C) 2008 Elsevier Inc. All rights reserved.