Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells.
Mitochondrial-targeted nitroxides disrupt mitochondrial architecture and inhibit expression of peroxiredoxin 3 and FOXM1 in malignant mesothelioma cells.
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DOI：
10.1002/jcp.24232
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发表时间：
2013-04
影响因子：
5.6
通讯作者：
Heintz, Nicholas H.
中科院分区：
文献类型：
--
作者：
Cunniff, Brian;Benson, Kira;Stumpff, Jason;Newick, Kheng;Held, Paul;Taatjes, Douglas;Joseph, Joy;Kalyanaraman, Balaraman;Heintz, Nicholas H.
恶性间皮瘤（MM）是腹膜和胸膜腔的顽固性肿瘤，主要与暴露于石棉有关。最近，我们描述了线粒体来源的氧化剂和FOXM1表达之间的相互作用，FOXM1是一种氧化还原反应性转录因子，已成为实体恶性肿瘤中有希望的治疗靶点。在这里，我们研究了通过三苯基磷（TPP）片段靶向线粒体的氮氧化物对培养的MM细胞线粒体氧化剂产生、FOXM1和过氧化物还蛋白3 （PRX3）的表达以及细胞活力的影响。Mito-carboxy-proxyl （MCP）和Mito-TEMPOL （MT）均引起线粒体氧化剂产生的剂量依赖性增加，并伴有FOXM1和PRX3表达的抑制和细胞活力的丧失。在同等浓度下，TPP、CP和TEMPOL对这些终点没有影响。利用氧化还原反应性绿色荧光蛋白靶向线粒体（mito-roGFP）的活细胞比例成像显示，MCP和MT，而不是CP、TEMPOL或TPP，能迅速诱导线粒体断裂和肿胀，形态转变与ATP水平降低和线粒体氧化剂产生增加有关。线粒体分裂抑制剂Mdivi-1不能使线粒体免于MCP的断裂。免疫荧光显微镜实验表明，一部分FOXM1与线粒体PRX3共存于细胞质中。我们的研究结果表明，MCP和MT通过线粒体结构明显破坏引起的氧化还原稳态扰动来抑制FOXM1表达和MM肿瘤细胞活力，并表明这两种化合物，无论是单独使用还是与硫链霉素或其他药物联合使用，都可能为MM的治疗提供可靠的选择。
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.
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影响因子：
11.8
作者：
Cassidy-Stone, Ann;Chipuk, Jerry E.;Nunnari, Jodi
通讯作者：
Nunnari, Jodi
影响因子：
4.6
作者：
Conour, JE;Graham, WV;Gaskins, HR
通讯作者：
Gaskins, HR
DOI：
10.1111/j.1432-1033.1994.tb19985.x
发表时间：
1994-01-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
FRIEDRICH, T;VANHEEK, P;WEISS, H
通讯作者：
WEISS, H
影响因子：
4.8
作者：
Hanson, GT;Aggeler, R;Remington, SJ
通讯作者：
Remington, SJ
影响因子：
8
作者：
Cannon, MB;Remington, SJ
通讯作者：
Remington, SJ