PDF(Pubmed)
Abstract：
Tamoxifen-resistant breast cancer cells (TamR-BCCs) are characterized by an enhanced metabolic phenotype compared to tamoxifen-sensitive cells. FoxO3a is an important modulator of cell metabolism, and its deregulation has been involved in the acquisition of tamoxifen resistance. Therefore, tetracycline-inducible FoxO3a was overexpressed in TamR-BCCs (TamR/TetOn-AAA), which, together with their control cell line (TamR/TetOn-V), were subjected to seahorse metabolic assays and proteomic analysis. FoxO3a was able to counteract the increased oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) observed in TamR by reducing their energetic activity and glycolytic rate. FoxO3a caused glucose accumulation, very likely by reducing LDH activity and mitigated TamR biosynthetic needs by reducing G6PDH activity and hindering NADPH production via the pentose phosphate pathway (PPP). Proteomic analysis revealed a FoxO3a-dependent marked decrease in the expression of LDH as well as of several enzymes involved in carbohydrate metabolism (e.g., Aldolase A, LDHA and phosphofructokinase) and the analysis of cBioPortal datasets of BC patients evidenced a significant inverse correlation of these proteins and FoxO3a. Interestingly, FoxO3a also increased mitochondrial biogenesis despite reducing mitochondrial functionality by triggering ROS production. Based on these findings, FoxO3a inducing/activating drugs could represent promising tools to be exploited in the management of patients who are refractory to antiestrogen therapy.
摘要：
与他莫昔芬敏感性细胞相比，他莫昔芬抗性乳腺癌细胞（TamR-BCC）的特征在于代谢表型增强。FoxO3a是细胞代谢的重要调节剂,它的放松管制已经参与了他莫昔芬抗性的获得。因此,四环素诱导的FoxO3a在TamR-BCCs（TamR/TetOn-AAA）中过度表达，which,连同它们的对照细胞系（TamR/TetOn-V），进行海马代谢测定和蛋白质组学分析。FoxO3a能够通过降低其能量活性和糖酵解速率来抵消TamR中观察到的耗氧率（OCR）和细胞外酸化率（ECAR）的增加。FoxO3a引起葡萄糖积累，很可能通过降低LDH活性并通过降低G6PDH活性和通过戊糖磷酸途径（PPP）阻碍NADPH产生来减轻TamR生物合成需求。蛋白质组学分析显示，LDH以及参与碳水化合物代谢的几种酶的表达呈FoxO3a依赖性显着下降（例如，醛缩酶A,LDHA和磷酸果糖激酶）以及对BC患者的cBioPortal数据集的分析证明了这些蛋白质与FoxO3a的显着负相关。有趣的是,尽管通过触发ROS产生降低了线粒体功能,FoxO3a也增加了线粒体生物发生。基于这些发现,FoxO3a诱导/激活药物可能代表有希望的工具，可用于治疗抗雌激素治疗难治性患者。
