Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Endocrinology. 2022 Jan 1;163(1). doi: 10.1210/endocr/bqab212.
Estrogen and estrogen receptor (ER) play a fundamental role in breast cancer. To support the rapid proliferation of ER+ breast cancer cells, estrogen increases glucose uptake and reprograms glucose metabolism. Meanwhile, estrogen/ER activates the anticipatory unfolded protein response (UPR) preparing cancer cells for the increased protein production required for subsequent cell proliferation. Here, we report that thioredoxin-interacting protein (TXNIP) is an important regulator of glucose metabolism in ER+ breast cancer cells, and estrogen/ER increases glucose uptake and reprograms glucose metabolism via activating anticipatory UPR and subsequently repressing TXNIP expression. In 2 widely used ER+ breast cancer cell lines, MCF7 and T47D, we showed that MCF7 cells express high TXNIP levels and exhibit mitochondrial oxidative phosphorylation (OXPHOS) phenotype, while T47D cells express low TXNIP levels and display aerobic glycolysis (Warburg effect) phenotype. Knockdown of TXNIP promoted glucose uptake and Warburg effect, while forced overexpression of TXNIP inhibited glucose uptake and Warburg effect. We further showed that estrogen represses TXNIP expression and activates UPR sensor inositol-requiring enzyme 1 (IRE1) via ER in the breast cancer cells, and IRE1 activity is required for estrogen suppression of TXNIP expression and estrogen-induced cell proliferation. Our study suggests that TXNIP is involved in estrogen-induced glucose uptake and metabolic reprogramming in ER+ breast cancer cells and links anticipatory UPR to estrogen reprogramming glucose metabolism.
雌激素和雌激素受体（ER）在乳腺癌中起着至关重要的作用。为了支持 ER+乳腺癌细胞的快速增殖，雌激素增加了葡萄糖摄取并重新编程了葡萄糖代谢。同时，雌激素/ER 激活了预期的未折叠蛋白反应（UPR），为随后细胞增殖所需的增加的蛋白质生产做好准备。在这里，我们报告硫氧还蛋白相互作用蛋白（TXNIP）是 ER+乳腺癌细胞中葡萄糖代谢的重要调节剂，雌激素/ER 通过激活预期的 UPR 并随后抑制 TXNIP 表达来增加葡萄糖摄取并重新编程葡萄糖代谢。在两种广泛使用的 ER+乳腺癌细胞系 MCF7 和 T47D 中，我们表明 MCF7 细胞表达高水平的 TXNIP 并表现出线粒体氧化磷酸化（OXPHOS）表型，而 T47D 细胞表达低水平的 TXNIP 并表现出有氧糖酵解（Warburg 效应）表型。TXNIP 的敲低促进了葡萄糖摄取和 Warburg 效应，而 TXNIP 的强制过表达抑制了葡萄糖摄取和 Warburg 效应。我们进一步表明，雌激素通过 ER 抑制乳腺癌细胞中 TXNIP 的表达并激活 UPR 传感器肌醇需求酶 1（IRE1），而 IRE1 活性是雌激素抑制 TXNIP 表达和雌激素诱导的细胞增殖所必需的。我们的研究表明，TXNIP 参与了雌激素诱导的 ER+乳腺癌细胞中的葡萄糖摄取和代谢重编程，并将预期的 UPR 与雌激素重新编程葡萄糖代谢联系起来。
