Scholzen Karoline C, Arnér Elias S J
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; Department of Selenoprotein Research and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary.
J Trace Elem Med Biol. 2025 Apr;88:127624. doi: 10.1016/j.jtemb.2025.127624. Epub 2025 Feb 17.
Selenium (Se), Copper (Cu) and Zinc (Zn) are essential trace elements, required for several cellular functions, showcasing toxicity in either insufficient or excessive concentrations. The selenoprotein thioredoxin reductase 1 (TXNRD1) is directly affected by Se availability and here we hypothesized that it may also be affected by high Cu and Zn concentrations.
Using an optimized protocol for the highly selective TXNRD1 activity probe, RX1, we discovered a direct inhibitory effect of Zn on the intracellular TXNRD1 activity, using two different commonly used human cancer cell lines, A549 lung carcinoma and HeLa cervical carcinoma cells. Subsequently, after initial inhibition by Zn, the TXNRD1 activity recovered in both cell lines, in HeLa cells concomitantly with activation of the redox regulatory transcription factor NRF2. High extracellular Cu concentrations did not induce an immediate decrease of intracellular TXNRD1 activity, but decreased its activity upon long-term exposure. While the expression levels of TXNRD1 did not change upon long-term Cu exposure, the selenoprotein glutathione peroxidase 1 (GPX1), that is more dependent upon selenocysteine incorporation, was downregulated, suggesting that higher Cu exposure generally impaired selenoprotein synthesis.
Our findings support the importance of understanding trace element exposure and availability in basic research, especially in redox biology research, as well as considering Cu and Zn as potential modulators of the cellular capacity of the thioredoxin system and other selenoproteins.
硒（Se）、铜（Cu）和锌（Zn）是必需的微量元素，参与多种细胞功能，在浓度不足或过高时均会表现出毒性。硒蛋白硫氧还蛋白还原酶1（TXNRD1）直接受硒可用性的影响，我们在此假设它也可能受到高浓度铜和锌的影响。
使用针对高选择性TXNRD1活性探针RX1的优化方案，我们利用两种常用的人类癌细胞系，即A549肺癌细胞和HeLa宫颈癌细胞，发现锌对细胞内TXNRD1活性具有直接抑制作用。随后，在锌的初始抑制作用后，两种细胞系中的TXNRD1活性均恢复，在HeLa细胞中，这与氧化还原调节转录因子NRF2的激活同时发生。高细胞外铜浓度并未立即导致细胞内TXNRD1活性降低，但长期暴露后其活性降低。虽然长期铜暴露后TXNRD1的表达水平没有变化，但更依赖于硒代半胱氨酸掺入的硒蛋白谷胱甘肽过氧化物酶1（GPX1）被下调，这表明更高的铜暴露通常会损害硒蛋白的合成。
我们的研究结果支持了在基础研究中理解微量元素暴露和可用性的重要性，特别是在氧化还原生物学研究中，以及将铜和锌视为硫氧还蛋白系统和其他硒蛋白细胞能力的潜在调节因子。
