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

ABSTRACT 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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Available from: Gerd Bobe, Sep 27, 2015
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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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    ABSTRACT: Background Both dietary and serum levels of inorganic phosphate (Pi) have been linked to development of cancer in experimental studies. This is the first population-based study investigating the relation between serum Pi and risk of cancer in humans. Methods From the Swedish Apolipoprotein Mortality Risk (AMORIS) study, we selected all participants (> 20 years old) with baseline measurements of serum Pi, calcium, alkaline phosphatase, glucose, and creatinine (n = 397,292). Multivariable Cox proportional hazards regression analyses were used to assess serum Pi in relation to overall cancer risk. Similar analyses were performed for specific cancer sites. Results We found a higher overall cancer risk with increasing Pi levels in men ( HR: 1.02 (95% CI: 1.00-1.04) for every SD increase in Pi), and a negative association in women (HR: 0.97 (95% CI: 0.96-0.99) for every SD increase in Pi). Further analyses for specific cancer sites showed a positive link between Pi quartiles and the risk of cancer of the pancreas, lung, thyroid gland and bone in men, and cancer of the oesophagus, lung, and nonmelanoma skin cancer in women. Conversely, the risks for developing breast and endometrial cancer as well as other endocrine cancer in both men and women were lower in those with higher Pi levels. Conclusions Abnormal Pi levels are related to development of cancer. Furthermore, the in verse association between Pi levels and risk of breast, endometrial and other endocrine cancers may indicate the role of hormonal factors in the relation between Pi metabolism and cancer.
    BMC Cancer 05/2013; 13(1):257. DOI:10.1186/1471-2407-13-257 · 3.36 Impact Factor
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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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    ABSTRACT: Novel therapeutic approaches are required for the treatment of osteosarcoma. Combination chemotherapy is receiving increased attention in order to identify compounds that may increase the therapeutic index of clinical anticancer drugs. In this regard, naturally occurring molecules with antitumor activity and with limited toxicity to normal tissues have been suggested as possible candidates for investigation of their synergistic efficacy in combination with antineoplastic drugs. Inorganic phosphate (Pi) is an essential nutrient for living organisms. Relevantly, Pi has emerged as an important signaling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression and protein abundance in many cell types. Previously, we showed that Pi inhibits proliferation and aggressiveness of U2OS human osteosarcoma cells and that Pi is capable of inducing sensitization of osteosarcoma cells to doxorubicin in a p53-dependent manner. In this study, we extended the role of Pi in the chemosensitivity of osteosarcoma cells to other anticancer drugs. Specifically, we report and compare the antiproliferative effects of a combination between Pi and doxorubicin, Taxol® and 5-fluorouracil (5-FU) treatments. We found that Pi increases the antiproliferative response to both Taxol and doxorubicin to a similar extent. On the other hand, Pi did not potentiate the anticancer effects induced by 5-FU. These effects were paralleled by apoptosis induction and were cell cycle-dependent. The clinical significance of our data and their potential therapeutic applications for improving osteosarcoma treatment are discussed.
    Oncology Reports 02/2013; 29(5). DOI:10.3892/or.2013.2306 · 2.30 Impact Factor
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    • "The control medium contained 0.916 mM Pi, and Pi concentrations listed in the figures are the final Pi medium concentrations. Added Pi was in the form of NaPO4, pH 7.4, from Sigma.10–13 "
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    ABSTRACT: Inorganic phosphate (Pi) is an essential nutrient for living organisms. It plays a key role in diverse physiological functions, including osteoblast differentiation and skeletal mineralization. Relevantly, Pi is emerging as an important signaling molecule capable of modulating multiple cellular functions by altering signal transduction pathways, gene expression, and protein abundance in many cell types. To our knowledge, the consequences of elevated Pi on behavior of breast cancer cells have been poorly addressed. In this study we investigate the effects of Pi on proliferation of MDA-MB-231 breast cancer cells. We report that Pi inhibits proliferation of MDA-MB-231 cells by slowing cell cycle progression, without apoptosis occurrence. We found that Pi causes cells to accumulate in G1 phase in a time-dependent manner. Accordingly, G1 accumulation was associated with a decrease of cyclin A and cyclin E and an increase of cell cycle inhibitors p21 and p27 protein levels, respectively. Moreover, the Pi-induced antiproliferative effect was dynamically accompanied by profound changes in ERK1/2 and STAT3 protein and phosphorylation levels in response to Pi. Altogether, our data represent the first evidence of Pi acting as a novel signaling molecule in MDA-MB-231 breast cancer cells, capable of eliciting a strong antiproliferative action and suggest that targeting Pi levels at local sites might represent the rationale for developing novel strategies for therapeutic intervention in triple-negative breast cancer.
    02/2013; 2(1):47-54. DOI:10.1089/biores.2012.0266
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