Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis.
Tamoxifen induces cellular stress in the nervous system by inhibiting cholesterol synthesis.
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他莫昔芬通过抑制胆固醇的合成来诱导神经系统中的细胞应激。
DOI：
10.1186/s40478-015-0255-6
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发表时间：
2015-11-26
影响因子：
7.1
通讯作者：
Ramer MS
中科院分区：
文献类型：
--
作者：
Denk F;Ramer LM;Erskine EL;Nassar MA;Bogdanov Y;Signore M;Wood JN;McMahon SB;Ramer MS
他莫昔芬 (TAM) 是一种重要的癌症治疗方法，也是利用诱导型 Cre-Lox 技术实现基因重组的实验工具。尽管它在临床和实验室中广泛使用，但我们对其对神经系统的影响知之甚少。这是一个值得关注的问题，因为 TAM 通过未知的机制引起人类认知障碍。细胞应激的一个标志是激活转录因子 3 (Atf3) 的诱导，因此为了确定 TAM 是否会在成人神经系统中诱导细胞应激，我们构建了一种敲入小鼠，其中 Atf3 启动子活性驱动 TAM 依赖性 Cre 重组酶 (Cre-ERT2) 的转录；当与 tdtomato 报告小鼠杂交时，Atf3 诱导会导致细胞产生强大且永久的基因标记，其中 Atf3 甚至会短暂上调。我们发现嗅球和齿状回的颗粒神经元、整个大脑的血管细胞和室管膜细胞以及外周感觉神经元响应 TAM 治疗而表达 tdtomato。我们还表明，TAM 通过抑制胆固醇环氧化物水解酶 (ChEH) 诱导 Atf3 上调：通过富含维生素 E 的小麦胚芽油（维生素 E 消耗 ChEH 底物）的递送来减轻报告基因的表达，并通过 ChEH 特异性抑制剂部分模拟。这项工作表明 TAM 对成人中枢和周围神经系统的细胞产生压力，并强调了对 TAM 临床和实验使用的担忧。我们建议在富含维生素 E 的载体（例如小麦胚芽油）中施用 TAM 作为一种简单的补救措施。
Tamoxifen (TAM) is an important cancer therapeutic and an experimental tool for effecting genetic recombination using the inducible Cre-Lox technique. Despite its widespread use in the clinic and laboratory, we know little about its effects on the nervous system. This is of significant concern because TAM, via unknown mechanisms, induces cognitive impairment in humans. A hallmark of cellular stress is induction of Activating Transcription Factor 3 (Atf3), and so to determine whether TAM induces cellular stress in the adult nervous system, we generated a knock-in mouse in which Atf3 promoter activity drives transcription of TAM-dependent Cre recombinase (Cre-ERT2); when crossed with tdtomato reporter mice, Atf3 induction results in robust and permanent genetic labeling of cells in which it is up-regulated even transiently. We found that granular neurons of the olfactory bulb and dentate gyrus, vascular cells and ependymal cells throughout the brain, and peripheral sensory neurons expressed tdtomato in response to TAM treatment. We also show that TAM induced Atf3 up-regulation through inhibition of cholesterol epoxide hydrolase (ChEH): reporter expression was mitigated by delivery in vitamin E-rich wheat germ oil (vitamin E depletes ChEH substrates), and was partially mimicked by a ChEH-specific inhibitor. This work demonstrates that TAM stresses cells of the adult central and peripheral nervous systems and highlights concerns about clinical and experimental use of TAM. We propose TAM administration in vitamin E-rich vehicles such as wheat germ oil as a simple remedy.