Elevated Phosphate Activates N-ras and Promotes Cell Transformation and Skin Tumorigenesis

Department of Medicine, Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Cancer Prevention Research (Impact Factor: 4.44). 02/2010; 3(3):359-70. DOI: 10.1158/1940-6207.CAPR-09-0068
Source: PubMed


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.

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    • "In the liver, vitamin D is metabolized to 25-hydroxy vitamin D (25 (OH) D), then further Vitamin D and some minerals in breast cancer 4075 Int J Clin Exp Pathol 2015;8(4):4074-4082 sis represents a potential factor contributing to the cell's prolific microenvironment [11]. "
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    International journal of clinical and experimental pathology 06/2015; 8(4):4074-4082. · 1.89 Impact Factor
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    • "In a study by Camalier and colleagues, female mouse models of skin tumorigenesis treated with high dietary Pi showed a 50% increase of tumor formation upon 7, 12-dimethylbenz[a]anthracene/12-O-tetradecanolyphorbol-13-acetate (DMBA/TPA) treatment compared to those treated with low Pi diet [5]. It was suggested that Pi affects the formation of skin tumours partly through increased activation of N-ras and its downstream targets [5]. For cancer of the brain/central nervous system, we observed no clear association with Pi levels, despite the reported effects of Pi on brain growth in animal studies. "
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    • "To further investigate the antitumor action of Pi in osteosarcoma cells, we analyzed the potential antitumor effects of a combination of Pi and other commonly used chemotherapeutic agents. To this purpose, we treated osteosarcoma U2OS cells with varying concentrations of Taxol and 5-FU, in the presence or absence of 5 mM Pi, a concentration covering the physiologic range in humans and in agreement with most of the published studies on Pi-triggered effects (15–19). Specific treatment conditions were examined encompassing exposure to no (0 mM, control), 0.5, 1, 5 μM Taxol, and 5, 10, 50 μM 5-FU in the presence or absence of 5 mM Pi for 24 h (28–31). "
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