硒是一种必需的微量元素，通过共翻译掺入具有重要生物学功能的硒蛋白中。长期以来，健康益处一直与补充硒有关。然而，过量摄入硒会产生细胞毒性。本研究的目的是研究正常人乳腺上皮细胞模型中对含硒氨基酸硒代蛋氨酸和硒代半胱氨酸反应的代谢途径。我们发现，在与癌性 MCF-7 和 Hela 细胞相同的浓度范围内，硒代蛋氨酸和硒代胱氨酸均能抑制非癌性 MCF-10A 细胞的增殖，从而导致细胞凋亡。 MCF-10A 细胞中的硒代胱氨酸暴露导致游离低分子量硫醇的严重消耗，这可能解释了观察到的氧化应激途径转录因子 NRF2 表达的上调。硒代蛋氨酸和硒代胱氨酸均诱导未折叠蛋白反应的靶基因（GRP78、ATF4、CHOP）的表达。使用针对内质网 (ER) 的氧化还原敏感荧光探针，我们发现两种硒氨基酸将 ER 氧化还原平衡转向氧化性更强的环境。这些结果表明，ER 氧化还原状态的改变可能会破坏蛋白质折叠，并导致暴露于硒氨基酸的 MCF-10A 细胞中 ER 应激诱导的细胞凋亡。© 2024。作者，获得 Springer Science Business Media 独家许可，LLC，施普林格自然的一部分。

Selenium is an essential trace element co-translationally incorporated into selenoproteins with important biological functions. Health benefits have long been associated with selenium supplementation. However, cytotoxicity is observed upon excessive selenium intake. The aim of this study is to investigate the metabolic pathways underlying the response to the selenium-containing amino acids selenomethionine and selenocysteine in a normal human breast epithelial cell model. We show that both selenomethionine and selenocystine inhibit the proliferation of non-cancerous MCF-10A cells in the same concentration range as cancerous MCF-7 and Hela cells, which results in apoptotic cell death. Selenocystine exposure in MCF-10A cells caused a severe depletion of free low molecular weight thiols, which might explain the observed upregulation of the expression of the oxidative stress pathway transcription factor NRF2. Both selenomethionine and selenocystine induced the expression of target genes of the unfolded protein response (GRP78, ATF4, CHOP). Using a redox-sensitive fluorescent probe targeted to the endoplasmic reticulum (ER), we show that both selenoamino acids shifted the ER redox balance towards an even more oxidizing environment. These results suggest that alteration of the redox state of the ER may disrupt protein folding and cause ER stress-induced apoptosis in MCF-10A cells exposed to selenoamino acids.© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.