Reduction of selenium-binding protein 1 sensitizes cancer cells to selenite via elevating extracellular glutathione: a novel mechanism of cancer-specific cytotoxicity of selenite.
Reduction of selenium-binding protein 1 sensitizes cancer cells to selenite via elevating extracellular glutathione: a novel mechanism of cancer-specific cytotoxicity of selenite.
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DOI：
10.1016/j.freeradbiomed.2014.11.015
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发表时间：
2015-02
影响因子：
7.4
通讯作者：
Yulei N. Wang;W. Fang;Ying Huang;Fen Hu;Qi Ying;Wancai Yang;B. Xiong
中科院分区：
文献类型：
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作者：
Yulei N. Wang;W. Fang;Ying Huang;Fen Hu;Qi Ying;Wancai Yang;B. Xiong
硒是一种必需的微量元素，已被广泛研究用于预防癌症。最近出现的证据也表明，超营养剂量的硒对癌细胞和化疗耐药细胞具有优先的细胞毒性，但其潜在的机制仍不清楚。本研究旨在探讨硒结合蛋白1 （SBP1）和谷胱甘肽过氧化物酶1 （GPX1）这两种不同的含硒蛋白代表在亚硒酸盐介导的癌症特异性细胞毒性中的作用。我们发现SBP1和GPX1蛋白水平在人乳腺癌和邻近匹配的非肿瘤组织中呈显著负相关（pearson = -0.4347，P=0.0338）。GPX1的异位表达通过下调SBP1增强亚硒酸盐的细胞毒性，SBP1可能是亚硒酸盐介导的细胞毒性的关键决定因素。亚硒酸盐暴露后，癌细胞和表柔比星耐药细胞中SBP1的减少导致过氧化氢和超氧阴离子的生成急剧增加，从而引起氧化应激并引发细胞凋亡。此外，通过小干扰RNA敲除SBP1，通过提高细胞外谷胱甘肽（GSH）来增加亚硒酸盐的敏感性，而细胞外谷胱甘肽（GSH）与亚硒酸盐自发反应，导致生长培养基中硒（IV）的快速消耗和亚硒酸盐的高亲和力摄取。综上所述，这些发现将提高我们对含硒蛋白在亚硒酸盐介导的细胞毒性中的作用的理解，并揭示了亚硒酸盐在癌细胞和耐药细胞中选择性细胞毒性的有效机制，其中SBP1可能通过调节细胞外GSH水平来调节细胞外微环境。
Selenium is an essential trace element and has been extensively studied for preventive effects on cancers. Recent emerging evidence has also shown that selenium at supranutritional dosage has a preferential cytotoxicity in cancer cells and chemotherapeutic drug-resistant cells, but the underlying mechanisms remain largely unknown. This study was to investigate the roles of two distinct representatives of selenium-containing proteins, selenium-binding protein 1 (SBP1) and glutathione peroxidase 1 (GPX1), in selenite-mediated cancer-specific cytotoxicity. We found that there was a significantly inverse correlation between SBP1 and GPX1 protein level in human breast cancers and adjacent matched nontumor tissues (Pearsonr=–0.4347,P=0.0338). Ectopic expression of GPX1 enhanced selenite cytotoxicity through down-regulation of SBP1, and SBP1 was likely to be a crucial determinant for selenite-mediated cytotoxicity. Reduction of SBP1 in cancer cells and epirubicin-resistant cells on selenite exposure resulted in a dramatic increase in the generation of hydrogen peroxide and superoxide anion, which in turn caused oxidative stress and triggered apoptosis. Furthermore, knockdown SBP1 by small interfering RNA increased selenite sensitivity by elevating extracellular glutathione (GSH), which spontaneously reacted with selenite and led to the rapid depletion of selenium (IV) in growth medium and the high-affinity uptake of selenite. In conclusion, these findings would improve our understanding of the roles of selenium-containing proteins in selenite-mediated cytotoxicity, and revealed a potent mechanism of the selective cytotoxicity of selenite in cancer cells and drug-resistant cells, in which SBP1 was likely to play an important role in modulating the extracellular microenvironment by regulating the levels of extracellular GSH.