Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
J Nucl Med. 2010 Nov;51(11):1740-7. doi: 10.2967/jnumed.110.074708. Epub 2010 Oct 18.
Use of (18)F-FDG uptake as a surrogate marker of therapeutic response requires the recognition of biologic factors that influence cancer cell glucose metabolism. Estrogen is a potent stimulator of breast cancer proliferation, a process that requires sufficient energy, which is likely met by increased glycolysis. We thus explored the effect of estrogen on (18)F-FDG uptake in responsive breast cancer cells and investigated the mediating molecular mechanisms.
T47D breast cancer cells were stimulated with 17β-estradiol (E(2)) or bovine serum albumin (BSA)-E(2) and measured for (18)F-FDG uptake, lactate release, and mitochondrial hexokinase activity. The effects of antiestrogens, cycloheximide, and major protein kinase inhibitors were investigated. Immunoblots were performed for membrane glucose transporter type 1, phosphorylated phosphatidylinositol 3-kinase (PI3K), and Akt.
E(2) augmented T47D cell (18)F-FDG uptake in a dose- and time-dependent manner that preceded and surpassed its proliferative effect. With exposure to 10 nM E(2), protein content-corrected (18)F-FDG uptake reached 172.7% ± 6.6% and 294.4% ± 9.5% of controls by 24 and 48 h, respectively. Lactate release reached 110.9% ± 7.3% and 145.2% ± 10.5% of controls at 24 and 48 h, and mitochondrial hexokinase activity increased to 187.1% ± 31.6% at 24 h. Membrane glucose transporter type 1 expression was unaltered. The effect was absent in estrogen receptor (ER)-negative breast cancer cells and was abrogated by ICI182780, indicating ER dependence. The E(2) effect was not blocked by tamoxifen and was mimicked by membrane-impermeable BSA-E(2), consistent with nongenomic membrane-initiated E(2) action. Inhibition by cycloheximide demonstrated the requirement of a new protein synthesis. Immunoblots displayed rapid phosphorylation of PI3K and Akt within minutes of E(2) treatment, and the specific PI3K inhibitors wortmannin and LY294002 abolished the ability of E(2) to elevate (18)F-FDG uptake.
Estrogen augments breast cancer cell (18)F-FDG uptake by stimulating glycolysis and hexokinase activity via membrane-initiated E(2) action that activates the PI3K-Akt pathway. These findings yield important insight into our understanding of the biology of breast cancer metabolism and may have potential implications for (18)F-FDG uptake as a surrogate marker of therapeutic response.
使用（18）F-FDG 摄取作为治疗反应的替代标志物，需要认识到影响癌细胞葡萄糖代谢的生物学因素。雌激素是乳腺癌增殖的有力刺激物，这一过程需要足够的能量，这可能通过增加糖酵解来满足。因此，我们探讨了雌激素对反应性乳腺癌细胞中（18）F-FDG 摄取的影响，并研究了介导的分子机制。
用 17β-雌二醇（E2）或牛血清白蛋白（BSA）-E2 刺激 T47D 乳腺癌细胞，并测量（18）F-FDG 摄取、乳酸释放和线粒体己糖激酶活性。研究了抗雌激素、环己酰亚胺和主要蛋白激酶抑制剂的作用。进行膜葡萄糖转运蛋白 1、磷酸化磷脂酰肌醇 3-激酶（PI3K）和 Akt 的免疫印迹。
E2 以剂量和时间依赖的方式增加 T47D 细胞（18）F-FDG 的摄取，先于并超过其增殖作用。用 10 nM E2 处理，蛋白含量校正的（18）F-FDG 摄取在 24 和 48 h 分别达到对照的 172.7%±6.6%和 294.4%±9.5%。乳酸释放在 24 和 48 h 分别达到对照的 110.9%±7.3%和 145.2%±10.5%，线粒体己糖激酶活性在 24 h 增加至 187.1%±31.6%。膜葡萄糖转运蛋白 1 表达不变。在雌激素受体（ER）阴性乳腺癌细胞中没有这种作用，并且被 ICI182780 阻断，表明其依赖于 ER。E2 作用不受他莫昔芬阻断，并被膜不可渗透的 BSA-E2 模拟，这与非基因组膜起始的 E2 作用一致。用环己酰亚胺抑制证明了新蛋白质合成的必要性。免疫印迹显示 E2 处理后几分钟内 PI3K 和 Akt 迅速磷酸化，特异性 PI3K 抑制剂wortmannin 和 LY294002 消除了 E2 升高（18）F-FDG 摄取的能力。
雌激素通过刺激糖酵解和己糖激酶活性来增加乳腺癌细胞（18）F-FDG 的摄取，这是通过膜起始的 E2 作用实现的，该作用激活了 PI3K-Akt 通路。这些发现深入了解了我们对乳腺癌代谢生物学的理解，并可能对（18）F-FDG 摄取作为治疗反应的替代标志物具有潜在意义。
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