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首页> 外文期刊>Journal of Cellular Physiology >Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells
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Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells

机译：Mitochondrial-targeted硝基氧干扰线粒体结构和抑制表达酶类3和FOXM1在恶性的间皮瘤细胞

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摘要

Malignant mesothelioma (MM) is an intractable tumor of the peritoneal and pleural cavities primarily linked to exposure to asbestos. Recently, we described an interplay between mitochondrial-derived oxidants and expression of FOXM1, a redox-responsive transcription factor that has emerged as a promising therapeutic target in solid malignancies. Here we have investigated the effects of nitroxides targeted to mitochondria via triphenylphosphonium (TPP) moieties on mitochondrial oxidant production, expression of FOXM1 and peroxiredoxin 3 (PRX3), and cell viability in MM cells in culture. Both Mito-carboxy-proxyl (MCP) and Mito-TEMPOL (MT) caused dose-dependent increases in mitochondrial oxidant production that was accompanied by inhibition of expression of FOXM1 and PRX3 and loss of cell viability. At equivalent concentrations TPP, CP, and TEMPOL had no effect on these endpoints. Live cell ratiometric imaging with a redox-responsive green fluorescent protein targeted to mitochondria (mito-roGFP) showed that MCP and MT, but not CP, TEMPOL, or TPP, rapidly induced mitochondrial fragmentation and swelling, morphological transitions that were associated with diminished ATP levels and increased production of mitochondrial oxidants. Mdivi-1, an inhibitor of mitochondrial fission, did not rescue mitochondria from fragmentation by MCP. Immunofluorescence microscopy experiments indicate a fraction of FOXM1 coexists in the cytoplasm with mitochondrial PRX3. Our results indicate that MCP and MT inhibit FOXM1 expression and MM tumor cell viability via perturbations in redox homeostasis caused by marked disruption of mitochondrial architecture, and suggest that both compounds, either alone or in combination with thiostrepton or other agents, may provide credible therapeutic options for the management of MM.
机译：恶性间皮瘤(MM)是一个棘手肿瘤腹膜、胸膜腔主要与暴露于石棉。最近,我们描述之间的相互作用mitochondrial-derived氧化剂和表达FOXM1 redox-responsive转录因子这已经成为一种很有前途的治疗目标坚实的恶性肿瘤。硝基氧的影响,有针对性的调查通过triphenylphosphonium线粒体(TPP)在线粒体半个氧化剂生产,FOXM1的表达和酶类3 (PRX3),在MM细胞和细胞生存能力的文化。Mito-carboxy-proxyl (MCP)和Mito-TEMPOL(太)在线粒体引起剂量依赖性增加伴随着氧化剂生产FOXM1 PRX3和抑制表达细胞生存能力的损失。TPP浓度、CP和TEMPOL没有效果在这些端点。redox-responsive绿色荧光蛋白针对线粒体(mito-roGFP)显示MCP和太,但不是CP、TEMPOL或TPP,迅速诱导线粒体碎片和肿胀,形态相关的转换ATP水平下降和增加线粒体氧化剂的生产。线粒体分裂的抑制剂,没有MCP救线粒体碎片。免疫荧光显微镜实验表明FOXM1在共存的一小部分细胞质和线粒体PRX3。表明MCP和抑制FOXM1表达式并通过扰动在毫米肿瘤细胞生存能力氧化还原体内平衡造成破坏线粒体结构,表明两种化合物,单独或结合thiostrepton或其他代理,可以提供可靠的治疗管理选项毫米。

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