Endocrinology, 2014, 155(9):3238-50.

Regulation of GLUT transporters by flavonoids in androgen-sensitive and insensitive prostate cancer cells

Pedro Gonzalez-Menendez, David Hevia, Aida Rodriguez Garcia, et al

Departamento de Morfologia y Biologia Celular, Instituto Universitario de Oncologia del Principado de Asturias, Universidad de Oviedo, Facultad de Medicina, 33006 Oviedo, Spain

Cancer cells show different metabolic requirements from normal cells. In prostate cancer, particularly, glycolytic metabolism differs in androgen-responsive and nonresponsive cells. In addition, some natural compounds with antiproliferative activities are able to modify glucose entry into cells by either modulating glucose transporter (GLUT) expression or by altering glucose binding. The aim of this work was to study the regulation of some GLUTs (GLUT1 and GLUT4) in both androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer cells by 4 structurally different flavonoids (ie, genistein, phloretin, apigenin, and daidzein). Glucose uptake was measured using nonradiolabeled 2-deoxyglucose. The evaluation of protein levels as well as subcellular distribution of GLUT1/4 were analyzed by Western blot and immunocytochemistry, respectively. Androgen-insensitive LNCaP-R and androgen-sensitive PC-3-AR cells were used to study the effect of androgen signaling. Additionally, a docking simulation was employed to compare interactions between flavonoids and XylE, a bacterial homolog of GLUT1 to -4. Results show for the first time the presence of functionally relevant GLUT4 in prostate cancer cells. Furthermore, differences in GLUT1 and GLUT4 levels and glucose uptake were found, without differences on subcellular distribution, after incubation with flavonoids. Docking simulation showed that all compounds interact with the same location of transporters. More importantly, differences between androgen-sensitive and -insensitive prostate cancer cells were found in both GLUT protein levels and glucose uptake. Thus, phenotypic characteristics of prostate cancer cells are responsible for the different effects of these flavonoids in glucose uptake and in GLUT expression rather than their structural differences, with the most effective in reducing cell growth being the highest in modifying glucose uptake and GLUT levels.

英国《内分泌学》，2014年9月

在雄激素敏感和不敏感的前列腺癌细胞中黄酮对GLUT运输的调节

佩德罗 冈萨雷斯  梅能德斯， 大卫 何伟亚， 阿依达 罗德里格斯 加西亚，等

西班牙德奥维耶多大学肿瘤研究所形态学和细胞生物学系

肿瘤细胞表现出与正常细胞不同的代谢需求。在前列腺癌中，特别地，是糖酵解代谢在雄激素响应和不响应细胞中不同。此外，一些具有抗增殖活性天然化合物能够通过两种调制的葡萄糖转运蛋白 (GLUT) 的表达或者改变葡萄糖成键方式修改葡萄糖进入细胞的途径。本研究的目的在于研究在雄激素敏感型 (LNCaP) 和不敏感(PC-3) 的前列腺癌细胞中，一些转运蛋白（GLUT1 和4）如何被4种结构不同的黄酮类化合物 （即，金雀异黄素、 根皮素、 芹菜素和大豆苷元）调节的。采用 非放射性同位素标记的2-脱氧葡萄糖测定葡萄糖的摄取量。用免疫印迹法和免疫细胞化学方法，分别测试蛋白质水平以及GLUT1/4的亚细胞分布。雄激素不敏感的 LNCaP-R 和雄激素敏感的PC-3-AR 细胞被用于研究雄激素信号通路的影响。此外，对接模拟试验方法被用来比较黄酮类化合物和 XylE，一种GLUT1 到-4的细菌同系物，之间的相互作用。结果首次表明在前列腺癌细胞中功能相关的 GLUT4 的存在。此外，在用黄酮类化合物培养后，G LUT1 和4 的蛋白水平和葡萄糖摄取量的差异被发现，没有发现亚细胞分布的差异。对接模仿实验表明所有化合物与转运蛋白的同一位置相互作用。更重要的是，雄激素敏感和不敏感的前列腺癌细胞的区别在于GLUT蛋白质水平和葡萄糖摄取量。因此，前列腺癌症细胞的表型特征与这些黄酮类化合物在葡萄糖摄取量和GLUT表达方面的不同作用相关，而不是结构上的差异，并且伴随着最有效地减少细胞生长，最大程度地修改葡萄糖摄取量和GLUT水平。