Nucleophosmin Regulates Intracellular Oxidative Stress Homeostasis via Antioxidant PRDX6
Nucleophosmin Regulates Intracellular Oxidative Stress Homeostasis via Antioxidant PRDX6
复制标题
核磷蛋白通过抗氧化剂 PRDX6 调节细胞内氧化应激稳态。
DOI：
10.1002/jcb.26135
复制
发表时间：
2017-12-01
影响因子：
4
通讯作者：
Li, Qi-Fu
中科院分区：
文献类型：
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作者：
Liu, Guo-Yan;Shi, Jing-Xian;Li, Qi-Fu
活性氧（ROS）在癌细胞中起着有害和有益的作用。核磷蛋白（NPM）与多种来源的癌症密切相关，其基因在实体瘤中过度表达或在血液恶性肿瘤中频繁突变。然而，NPM在氧化应激中的作用和调节机制尚不清楚。本研究发现，NPM通过调节巯基特异性抗氧化蛋白家族成员过氧化物氧还蛋白6（peroxiredoxin 6，PRDX 6）的表达，从而影响ROS的水平和分布。我们的数据表明，NPM敲低导致ROS的增加，并从细胞质迁移到核质。相反，NPM的过表达或细胞质定位上调PRDX 6，并降低ROS。此外，NPM敲低降低了过氧化物氧还蛋白家族蛋白，包括PRDX 1、PRDX 4和PRDX 6。免疫共沉淀进一步证实了PRDX 6和NPM之间的相互作用。此外，NSC 348884，一种特异性靶向NPM寡聚化的抑制剂，降低PRDX 6并显著上调ROS。这些观察结果表明NPM的表达和定位通过PRDX 6蛋白影响肿瘤细胞中氧化应激的稳态平衡。NPM/PRDX/ROS调控轴可能为肿瘤治疗提供新的治疗靶点。J.细胞。118：4697-4707，2017. (c)2017 Wiley Periodicals，Inc.
Reactive oxygen species (ROS) play both deleterious and beneficial roles in cancer cells. Nucleophosmin (NPM) is heavily implicated in cancers of diverse origins, being its gene over-expression in solid tumors or frequent mutations in hematological malignancies. However, the role and regulatory mechanism of NPM in oxidative stress are unclear. Here, we found that NPM regulated the expression of peroxiredoxin 6 (PRDX6), a member of thiol-specific antioxidant protein family, consequently affected the level and distribution of ROS. Our data indicated that NPM knockdown caused the increase of ROS and its relocation from cytoplasm to nucleoplasm. In contrast, overexpression or cytoplasmic localization of NPM upregulated PRDX6, and decreased ROS. In addition, NPM knockdown decreased peroxiredoxin family proteins, including PRDX1, PRDX4, and PRDX6. Co-immunoprecipitation further confirmed the interaction between PRDX6 and NPM. Moreover, NSC348884, an inhibitor specifically targeting NPM oligomerization, decreased PRDX6 and significantly upregulated ROS. These observations demonstrated that the expression and localization of NPM affected the homeostatic balance of oxidative stress in tumor cells via PRDX6 protein. The regulation axis of NPM/PRDX/ROS may provide a novel therapeutic target for cancer treatment. J. Cell. Biochem. 118: 4697-4707, 2017. (c) 2017 Wiley Periodicals, Inc.