Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species.
Overexpression of Lon contributes to survival and aggressive phenotype of cancer cells through mitochondrial complex I-mediated generation of reactive oxygen species.
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DOI：
10.1038/cddis.2013.204
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发表时间：
2013-06-20
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
Lon 蛋白酶是一种多功能蛋白质，在线粒体的蛋白质质量控制和应激反应途径中发挥作用。人类 Lon 在代表癌症应激表型的氧化和缺氧应激下上调。然而，很少有文献对Lon的致瘤作用进行全面、详细的研究。 Lon 的过度表达可促进细胞增殖、细胞凋亡对应激的抵抗力和转化。此外，Lon 过度表达会诱导线粒体活性氧 (ROS) 的产生，这是由于 Lon 介导的 NDUFS8（电子传递链复合物 I 中的线粒体 Fe-S 蛋白）的上调所致。线粒体 ROS 水平的增加通过丝裂原激活蛋白激酶 (MAPK) 和 Ras-ERK 激活促进细胞增殖、细胞存活、细胞迁移和上皮间质转化。总体而言，本报告首次证明了 Lon 过度表达在肿瘤发生中的作用。 Lon 过度表达赋予细胞凋亡抗应激能力，并通过复合物 I 作为信号分子诱导线粒体 ROS 产生，从而激活 Ras 和 MAPK 信号传导，从而赋予癌细胞生存优势和适应能力。最后，计算机和免疫组织化学分析表明，Lon 在包括口腔癌在内的各种类型的癌症组织中特异性过度表达。
Lon protease is a multifunction protein and operates in protein quality control and stress response pathways in mitochondria. Human Lon is upregulated under oxidative and hypoxic stresses that represent the stress phenotypes of cancer. However, little literature undertakes comprehensive and detailed investigations on the tumorigenic role of Lon. Overexpression of Lon promotes cell proliferation, apoptotic resistance to stresses, and transformation. Furthermore, Lon overexpression induces the production of mitochondrial reactive oxygen species (ROS) that result from Lon-mediated upregulation of NDUFS8, a mitochondrial Fe-S protein in complex I of electron transport chain. Increased level of mitochondrial ROS promotes cell proliferation, cell survival, cell migration, and epithelial–mesenchymal transition through mitogen-activated protein kinase (MAPK) and Ras-ERK activation. Overall, the present report for the first time demonstrates the role of Lon overexpression in tumorigenesis. Lon overexpression gives an apoptotic resistance to stresses and induces mitochondrial ROS production through Complex I as signaling molecules to activate Ras and MAPK signaling, giving the survival advantages and adaptation to cancer cells. Finally, in silico and immunohistochemistry analysis showed that Lon is overexpressed specifically in various types of cancer tissue including oral cancer.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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DOI：
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发表时间：
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影响因子：
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DOI：
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发表时间：
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期刊：
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影响因子：
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