Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Cancer Prev Res (Phila). 2010 Mar;3(3):359-70. doi: 10.1158/1940-6207.CAPR-09-0068. Epub 2010 Feb 9.
Recent results suggest a paradigm shift from viewing inorganic phosphate as a passive requirement for basic cell functions to an active regulator of cell behavior. We have previously shown that elevated concentrations of phosphate increased cell proliferation and expression of protumorigenic genes such as Fra-1 and osteopontin in a preosteoblast cell line. Therefore, we hypothesized that elevated phosphate concentrations would promote cell transformation in vitro and tumorigenesis in vivo. Supplementation of medium with phosphate increased anchorage-independent transformation and proliferation of BALB/c mouse JB6 epidermal cells, activation of N-ras, ERK1/2, and activator protein-1, and increased gene expression of Fra-1, COX-2, and osteopontin in a dose-dependent manner. These in vitro results led to the hypothesis that varying the levels of dietary inorganic phosphate would alter tumorigenesis in the mouse model of skin carcinogenesis. Female FVB/N mice were treated with 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate and fed high- or low-phosphate diets (1.2% versus 0.2% of the diet) for 19 weeks. The high-phosphate diet increased skin papilloma number by approximately 50% without changing feed intake and body weights. High dietary phosphate increased serum concentrations of phosphate, parathyroid hormone, and osteopontin and decreased serum concentrations of calcium. Thus, we conclude that elevated phosphate promotes cell transformation and skin tumorigenesis partly by increasing the availability of phosphate for activation of N-ras and its downstream targets, which defines reducing dietary phosphate as a novel target for chemoprevention.
最近的研究结果表明，人们对于无机磷酸盐的认识正在发生转变，其不再被视为细胞基本功能的被动需求，而是细胞行为的一种主动调节剂。我们之前已经证明，在成骨前体细胞系中，磷酸盐浓度的升高会增加细胞增殖和促肿瘤基因（如 Fra-1 和骨桥蛋白）的表达。因此，我们假设磷酸盐浓度的升高会促进体外细胞转化和体内肿瘤发生。在培养基中添加磷酸盐会增加 BALB/c 小鼠 JB6 表皮细胞的无锚定依赖性转化和增殖，激活 N-ras、ERK1/2 和激活蛋白-1，并以剂量依赖的方式增加 Fra-1、COX-2 和骨桥蛋白的基因表达。这些体外研究结果使我们提出了这样的假设，即改变饮食中无机磷酸盐的水平会改变皮肤致癌模型中小鼠的肿瘤发生。雌性 FVB/N 小鼠接受 7,12-二甲基苯并(a)蒽/12-O-十四烷酰佛波醇-13-醋酸酯处理，并在 19 周内喂食高或低磷酸盐饮食（饮食中的 1.2%与 0.2%）。高磷酸盐饮食使皮肤乳头状瘤的数量增加了约 50%，而不改变饲料摄入量和体重。高膳食磷酸盐增加了血清磷酸盐、甲状旁腺激素和骨桥蛋白的浓度，降低了血清钙的浓度。因此，我们得出结论，磷酸盐水平升高通过增加 N-ras 及其下游靶标激活所需的磷酸盐的可用性来促进细胞转化和皮肤肿瘤发生，这表明降低膳食磷酸盐是化学预防的一个新靶点。
