Pacific Biosciences Research Center, University of Hawaii at Manoa, Honolulu, HI 96822, USA.
Biomolecules. 2022 Oct 28;12(11):1581. doi: 10.3390/biom12111581.
A potential target of precision nutrition in cancer therapeutics is the micronutrient selenium (Se). Se is metabolized and incorporated as the amino acid selenocysteine (Sec) into 25 human selenoproteins, including glutathione peroxidases (GPXs) and thioredoxin reductases (TXNRDs), among others. Both the processes of Se and Sec metabolism for the production of selenoproteins and the action of selenoproteins are utilized by cancer cells from solid tumors as a protective mechanism against oxidative damage and to resist ferroptosis, an iron-dependent cell death mechanism. Protection against ferroptosis in cancer cells requires sustained production of the selenoprotein GPX4, which involves increasing the uptake of Se, potentially activating Se metabolic pathways such as the trans-selenation pathway and the TXNRD1-dependent decomposition of inorganic selenocompounds to sustain GPX4 synthesis. Additionally, endoplasmic reticulum-resident selenoproteins also affect apoptotic responses in the presence of selenocompounds. Selenoproteins may also help cancer cells adapting against increased oxidative damage and the challenges of a modified nutrient metabolism that result from the Warburg switch. Finally, cancer cells may also rewire the selenoprotein hierarchy and use Se-related machinery to prioritize selenoproteins that are essential to the adaptations against ferroptosis and oxidative damage. In this review, we discuss both the evidence and the gaps in knowledge on how cancer cells from solid tumors use Se, Sec, selenoproteins, and the Se-related machinery to promote their survival particularly via resistance to ferroptosis.
精准营养在癌症治疗中的一个潜在靶点是微量元素硒（Se）。Se 被代谢并整合到 25 个人类硒蛋白中，包括谷胱甘肽过氧化物酶（GPXs）和硫氧还蛋白还原酶（TXNRDs）等，作为氨基酸硒代半胱氨酸（Sec）。硒和 Sec 代谢生成硒蛋白的过程以及硒蛋白的作用都被实体瘤中的癌细胞利用，作为防止氧化损伤和抵抗铁死亡的保护机制，铁死亡是一种依赖铁的细胞死亡机制。为了防止铁死亡，癌细胞需要持续产生硒蛋白 GPX4，这涉及到增加 Se 的摄取，可能会激活 Se 代谢途径，如转硒途径和 TXNRD1 依赖的无机硒化合物分解，以维持 GPX4 的合成。此外，内质网驻留的硒蛋白也会影响有硒化合物存在时的细胞凋亡反应。硒蛋白还可能帮助癌细胞适应氧化损伤的增加和由于瓦博格效应导致的改变的营养代谢的挑战。最后，癌细胞也可能重新调整硒蛋白的层次结构，并利用与 Se 相关的机制来优先选择对铁死亡和氧化损伤适应至关重要的硒蛋白。在这篇综述中，我们讨论了实体瘤中的癌细胞如何利用 Se、Sec、硒蛋白和与 Se 相关的机制来促进其生存，特别是通过抵抗铁死亡的证据和知识差距。
