Estradiol Stimulates Glucose Metabolism via 6-Phosphofructo-2-kinase ( PFKFB3)
Estradiol Stimulates Glucose Metabolism via 6-Phosphofructo-2-kinase ( PFKFB3)
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DOI：
10.1074/jbc.m113.529990
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发表时间：
2014-03-28
影响因子：
4.8
通讯作者：
Chesney, Jason
中科院分区：
文献类型：
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作者：
Imbert-Fernandez, Yoannis;Clem, Brian F.;Chesney, Jason
背景：雌二醇对葡萄糖代谢的调节作用尚不明确。结果：我们发现雌二醇刺激葡萄糖代谢的部分原因是通过刺激PFKFB3产生果糖2,6-二磷酸。结论：PFKFB3是雌二醇刺激葡萄糖代谢所需的下游靶点。意义：联合靶向PFKFB3和雌激素受体可能对ER+ IV期乳腺癌患者有益。雌激素受体阳性（ER+）乳腺癌患者服用雌二醇（E2）可刺激肿瘤对葡萄糖的摄取。重要的是，这种E2诱导的代谢耀斑可以预测抗雌激素的临床有效性，因此E2的下游代谢调节因子有望作为抗乳腺癌药物开发的靶点。6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶家族（PFKFB1-4）通过其产物果糖-2,6-二磷酸（F26BP）控制糖酵解通量，而果糖-2,6-二磷酸（F26BP）激活6-磷酸果糖-1激酶（PFK-1）。我们假设E2可能促进PFKFB3的表达，导致F26BP和葡萄糖摄取增加。我们证明，相对于正常乳腺组织，PFKFB3在III期淋巴结转移中表达最高，并且人MCF-7乳腺癌细胞暴露于E2会导致[C-14]葡萄糖摄取和糖酵解迅速增加，这与PFKFB3 mRNA（通过ER与其启动子结合）、蛋白表达及其产物F26BP的细胞内浓度的诱导一致。重要的是，使用siRNA或PFKFB3抑制剂选择性抑制PFKFB3的表达和活性可显著降低e2介导的F26BP、[C-14]葡萄糖摄取和糖酵解的增加。此外，MCF-7细胞与PFKFB3抑制剂和抗雌激素ICI 182780共同处理可协同诱导凋亡细胞死亡。这些发现首次证明了雌激素受体直接促进PFKFB3 mRNA转录，而这反过来又是乳腺癌细胞葡萄糖代谢和存活所必需的。重要的是，这些结果提供了必要的临床前信息，可能允许最终设计PFKFB3拮抗剂与抗雌激素治疗在ER+ IV期乳腺癌患者中的组合试验。
Background: The regulation of glucose metabolism by estradiol is poorly defined. Results: We find that estradiol stimulates glucose metabolism in part by stimulating the production of fructose 2,6-bisphosphate by PFKFB3. Conclusion: PFKFB3 is a downstream target of estradiol required to stimulate glucose metabolism. Significance: Combined targeting of PFKFB3 and the estrogen receptor may prove beneficial to ER+ stage IV breast cancer patients.Estradiol (E2) administered to estrogen receptor-positive (ER+) breast cancer patients stimulates glucose uptake by tumors. Importantly, this E2-induced metabolic flare is predictive of the clinical effectiveness of anti-estrogens and, as a result, downstream metabolic regulators of E2 are expected to have utility as targets for the development of anti-breast cancer agents. The family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) control glycolytic flux via their product, fructose-2,6-bisphosphate (F26BP), which activates 6-phosphofructo-1-kinase (PFK-1). We postulated that E2 might promote PFKFB3 expression, resulting in increased F26BP and glucose uptake. We demonstrate that PFKFB3 expression is highest in stage III lymph node metastases relative to normal breast tissues and that exposure of human MCF-7 breast cancer cells to E2 causes a rapid increase in [C-14]glucose uptake and glycolysis that is coincident with an induction of PFKFB3 mRNA (via ER binding to its promoter), protein expression and the intracellular concentration of its product, F26BP. Importantly, selective inhibition of PFKFB3 expression and activity using siRNA or a PFKFB3 inhibitor markedly reduces the E2-mediated increase in F26BP, [C-14]glucose uptake, and glycolysis. Furthermore, co-treatment of MCF-7 cells with the PFKFB3 inhibitor and the anti-estrogen ICI 182,780 synergistically induces apoptotic cell death. These findings demonstrate for the first time that the estrogen receptor directly promotes PFKFB3 mRNA transcription which, in turn, is required for the glucose metabolism and survival of breast cancer cells. Importantly, these results provide essential preclinical information that may allow for the ultimate design of combinatorial trials of PFKFB3 antagonists with anti-estrogen therapies in ER+ stage IV breast cancer patients.