Cox Andrew G, Brown Kristin K, Arner Elias S J, Hampton Mark B
Free Radical Research Group, Department of Pathology, University of Otago, Christchurch, New Zealand.
Biochem Pharmacol. 2008 Oct 30;76(9):1097-109. doi: 10.1016/j.bcp.2008.08.021. Epub 2008 Aug 26.
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 (I) 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.
硫氧还蛋白还原酶(TrxR)是一种关键的硒蛋白抗氧化酶,也是抗癌药物的潜在靶点。TrxR的一种有效抑制剂是金(I)化合物金诺芬,它可触发线粒体依赖性凋亡途径。金诺芬诱导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核心事件。我们评估了用金诺芬处理的Jurkat T淋巴瘤细胞中过氧化物还原酶(Prx)的氧化还原状态,发现线粒体Prx3比胞质Prx1和2对氧化更敏感,表明存在选择性线粒体应激。在几种细胞类型中,在金诺芬的凋亡剂量下检测到Prx3氧化,且发生在包括细胞色素c释放和线粒体去极化在内的其他线粒体事件之前。金诺芬还能使U937细胞对TNF-α介导的凋亡敏感。Bcl-2的过表达有效阻断了金诺芬诱导的凋亡,Bax/Bak缺陷的小鼠胚胎成纤维细胞也对凋亡有抗性,表明该家族的促凋亡蛋白在金诺芬触发的凋亡中起核心作用。金诺芬处理抑制了凋亡抗性细胞的增殖,在更高剂量的金诺芬作用下可通过坏死导致细胞死亡。我们得出结论,金诺芬通过与Prx3氧化相结合的选择性破坏线粒体氧化还原稳态相关的Bax/Bak依赖性机制诱导细胞凋亡。