Peroxiredoxin 3 is a redox-dependent target of thiostrepton in malignant mesothelioma cells.
Peroxiredoxin 3 is a redox-dependent target of thiostrepton in malignant mesothelioma cells.
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DOI：
10.1371/journal.pone.0039404
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Heintz N
中科院分区：
文献类型：
--
作者：
Newick K;Cunniff B;Preston K;Held P;Arbiser J;Pass H;Mossman B;Shukla A;Heintz N
硫链菌素(thiostrepton，TS)是一种噻唑类抗生素，可抑制FOXM1的表达，FOXM1是细胞周期进展和抵抗癌基因诱导的氧化应激所必需的致癌转录因子。TS的作用机制尚不清楚，增强TS活性的策略将改善其治疗潜力。对人类肿瘤样本的分析表明，FOXM1在恶性间皮瘤(MM)中广泛表达，这是一种与石棉暴露相关的顽固性肿瘤。在人MM细胞培养模型上研究了TS的作用机制。对于其他类型的肿瘤细胞，TS以剂量依赖的方式抑制MM细胞FOXM1的表达。抗氧化剂N-乙酰-L-半胱氨酸(NAC)预先与细胞孵育可阻断TS对FXM1表达的抑制和ERK1/2的激活，表明TS在MM细胞中的作用机制是氧化还原依赖的。对线粒体硫氧还蛋白还原酶2(TR2)-硫氧还蛋白2(TRX2)-过氧化还蛋白3(PRX3)抗氧化网络的检测表明，TS改变了PRX3的电泳率。重组人PRX3与TS体外孵育也导致PRX3的凝胶迁移率发生改变。修饰后的PRX3细胞和重组菌体对二硫苏糖醇和十二烷基硫酸钠均有抗性，并被NAC抑制，表明TS共价加合了PRX3中的半胱氨酸残基。阳离子三苯甲烷龙胆紫(GV)降低内源性线粒体TRX2水平，可促进TS对PRX3的修饰，显著增强其细胞毒活性。我们的结果表明，TS共价加成了PRX3，从而使一个主要的线粒体抗氧化网络失效，该网络对抗慢性线粒体氧化应激。像GV这样的氧化还原活性化合物可以改变TR2/TRX2网络，从而显著提高TS的疗效，从而提供一种组合方法，利用线粒体功能中氧化还原依赖的扰动作为间皮瘤的治疗方法。
Thiostrepton (TS) is a thiazole antibiotic that inhibits expression of FOXM1, an oncogenic transcription factor required for cell cycle progression and resistance to oncogene-induced oxidative stress. The mechanism of action of TS is unclear and strategies that enhance TS activity will improve its therapeutic potential. Analysis of human tumor specimens showed FOXM1 is broadly expressed in malignant mesothelioma (MM), an intractable tumor associated with asbestos exposure. The mechanism of action of TS was investigated in a cell culture model of human MM. As for other tumor cell types, TS inhibited expression of FOXM1 in MM cells in a dose-dependent manner. Suppression of FOXM1 expression and coincidental activation of ERK1/2 by TS were abrogated by pre-incubation of cells with the antioxidant N-acetyl-L-cysteine (NAC), indicating its mechanism of action in MM cells is redox-dependent. Examination of the mitochondrial thioredoxin reductase 2 (TR2)-thioredoxin 2 (TRX2)-peroxiredoxin 3 (PRX3) antioxidant network revealed that TS modifies the electrophoretic mobility of PRX3. Incubation of recombinant human PRX3 with TS in vitro also resulted in PRX3 with altered electrophoretic mobility. The cellular and recombinant species of modified PRX3 were resistant to dithiothreitol and SDS and suppressed by NAC, indicating that TS covalently adducts cysteine residues in PRX3. Reduction of endogenous mitochondrial TRX2 levels by the cationic triphenylmethane gentian violet (GV) promoted modification of PRX3 by TS and significantly enhanced its cytotoxic activity. Our results indicate TS covalently adducts PRX3, thereby disabling a major mitochondrial antioxidant network that counters chronic mitochondrial oxidative stress. Redox-active compounds like GV that modify the TR2/TRX2 network may significantly enhance the efficacy of TS, thereby providing a combinatorial approach for exploiting redox-dependent perturbations in mitochondrial function as a therapeutic approach in mesothelioma.
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