PDF(Pubmed)
Abstract：
Background: Tamoxifen is commonly used in the treatment of hormonal-positive breast cancer. However, 30%-40% of tumors treated with tamoxifen develop resistance; therefore, an important step to overcome this resistance is to understand the underlying molecular and metabolic mechanisms. In the present work, we used metabolic profiling to determine potential biomarkers of tamoxifen resistance, and gene expression levels of enzymes important to these metabolites and then correlated the expression to the survival of patients receiving tamoxifen. Methods: Tamoxifen-resistant cell lines previously developed and characterized in our laboratory were metabolically profiled with nuclear magnetic resonance spectroscopy (NMR) using cryogenic probe, and the findings were correlated with the expression of genes that encode the key enzymes of the significant metabolites. Moreover, the effect of significantly altered genes on the overall survival of patients was assessed using the Kaplan-Meier plotter web tool. Results: We observed a significant increase in the levels of glutamine, taurine, glutathione, and xanthine, and a significant decrease in the branched-chain amino acids, valine, and isoleucine, as well as glutamate and cysteine in the tamoxifen-resistant cells compared to tamoxifen sensitive cells. Moreover, xanthine dehydrogenase and glutathione synthase gene expression were downregulated, whereas glucose-6-phosphate dehydrogenase was upregulated compared to control. Additionally, increased expression of xanthine dehydrogenase was associated with a better outcome for breast cancer patients. Conclusion: Overall, this study sheds light on metabolic pathways that are dysregulated in tamoxifen-resistant cell lines and the potential role of each of these pathways in the development of resistance.
摘要：
背景：他莫昔芬常用于治疗激素阳性乳腺癌。然而,用他莫昔芬治疗的肿瘤中有30％-40％会产生耐药性；因此，克服这种抗性的一个重要步骤是了解潜在的分子和代谢机制。在目前的工作中,我们使用代谢谱来确定他莫昔芬耐药性的潜在生物标志物，和对这些代谢物重要的酶的基因表达水平，然后将表达与接受他莫昔芬的患者的生存相关联。方法：使用低温探针用核磁共振波谱（NMR）对先前在我们实验室开发和表征的三苯氧胺抗性细胞系进行代谢分析，并且该发现与编码重要代谢物关键酶的基因的表达相关。此外，使用Kaplan-Meier绘图仪网络工具评估了显著改变的基因对患者总生存期的影响.结果：我们观察到谷氨酰胺水平显着增加，牛磺酸,谷胱甘肽,和黄嘌呤,支链氨基酸的显著减少，缬氨酸,和异亮氨酸,与他莫昔芬敏感细胞相比，他莫昔芬耐药细胞中的谷氨酸和半胱氨酸。此外，黄嘌呤脱氢酶和谷胱甘肽合成酶基因表达下调，而葡萄糖-6-磷酸脱氢酶与对照相比上调。此外,黄嘌呤脱氢酶的表达增加与乳腺癌患者的预后改善相关.结论：总体而言，这项研究揭示了他莫昔芬耐药细胞系中失调的代谢途径，以及这些途径在耐药性发展中的潜在作用。
