Article

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: 5.27). 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.

Download full-text

Full-text

Available from: Gerd Bobe, Aug 23, 2015
0 Followers
 · 
104 Views
  • Source
    • "Results Pi inhibits proliferation of p53-wild type human osteosarcoma U2OS cells through a slowing-down of cell division cycle and not apoptosis occurrence We have previously shown that inorganic phosphate (Pi) inhibits dose-dependently proliferation of human osteosarcoma U2OS cells via an adenylate cyclase/cAMPmediated mechanism (Naviglio et al., 2006). Throughout our studies, we have used a spectrum of final concentration of Pi to cover the physiologic range in humans and in agreement with most of the published studies on Pi-triggered effects (Naviglio et al., 2006, 2011; Camalier et al., 2010; Khoshniat et al., 2011). To evaluate the possible role of p53 in Pi-induced growth suppressive effect in U2OS cells, first we looked at the impact of inorganic phosphate on proliferation of osteosarcoma cells with different status of endogenous p53. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Osteosarcoma is the most common malignant primary bone tumor in children and adolescents. The clinical outcome for osteosarcoma remains discouraging despite aggressive surgery and intensive radiotherapy and chemotherapy regimens. Thus, novel therapeutic approaches are needed. Previously, we have shown that inorganic phosphate (Pi) inhibits proliferation and aggressiveness of human osteosarcoma U2OS cells identifying adenylate cyclase, beta3 integrin, Rap1, ERK1/2 as proteins whose expression and function are relevantly affected in response to Pi. In this study, we investigated whether Pi could affect chemosensitivity of osteosarcoma cells and the underlying molecular mechanisms. Here, we report that Pi inhibits proliferation of p53-wild type U2OS cells (and not of p53-null Saos and p53-mutant MG63 cells) by slowing-down cell cycle progression, without apoptosis occurrence. Interestingly, we found that Pi strongly enhances doxorubicin-induced cytotoxicity in U2OS, and not in Saos and MG63 cells, by apoptosis induction, as revealed by a marked increase of sub-G1 population, Bcl-2 downregulation, caspase-3 activation, and PARP cleavage. Remarkably, Pi/doxorubicin combination-induced cytotoxicity was accompanied by an increase of p53 protein levels and of p53 target genes mdm2, p21 and Bax, and was significantly reduced by the p53 inhibitor pifithrine-alpha. Moreover, the doxorubicin-induced cytotoxicity was associated with ERK1/2 pathway inhibition in response to Pi. Altogether, our data enforce the evidence of Pi as a novel signaling molecule capable of inhibiting ERK pathway and inducing sensitization to doxorubicin of osteosarcoma cells by p53-dependent apoptosis, implying that targeting Pi levels might represent a rational strategy for improving osteosarcoma therapy. J. Cell. Physiol. 228: 198-206, 2013. © 2012 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 01/2013; 228(1):198-206. DOI:10.1002/jcp.24124 · 3.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin D and calcium are involved in a wide range of proliferation, apoptosis and cell signaling activities in the body. Suboptimal concentrations may lead to cancer development. The role of phosphate in cancer metabolism is particularly relevant in breast cancer while, magnesium deficiency favors DNA mutations leading to carcinogenesis. To determine serum levels of vitamin D, calcium, phosphorus, magnesium, and parathormone in female breast cancer patients and to assess their association with some prognostic factors in breast cancer. This study is done on 98 newly diagnosed female breast cancer patients and 49 age matched apparently healthy female volunteers as controls. Serum samples from all patients and controls were subjected to 25-OH Vit D, calcium, phosphorus, magnesium, and parathormone measurements. In the breast cancer group, the median serum levels of 25-OH Vit D were 15 ng/ml, while it was 21 ng/ml in the control group. Levels of 25-OH Vit D and other tested minerals were significantly lower while calcium:magnesium (Ca:Mg) ratio, and calcium:phosphorus (Ca:P) ratio were significantly higher in the breast cancer group. Significant negative correlation was detected between phosphorus and calcium, ionized calcium , calcium magnesium ratio, and calcium phosphorus ratio. It is not only the deficient levels of Vit D and other related minerals, but the combination of the abnormal levels of all the studied parameters that might contribute to the development of cancer. Further studies with larger number of patient are needed.
    International journal of clinical and experimental pathology 8(4):4074-4082. · 1.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Image data are noisy samples acquired at discrete positions. Signal processing explicitly or implicitly involves some kind of interpolation to match a desired point spread function (PSF), to match a certain spatial resolution or to match certain contrast detection criteria. By optimization of a resolution-, noise- and dose-dependent figure of merit it was recently shown that a given spatial resolution can be best achieved using detector elements far smaller than the desired resolution element. A potential dose reduction in the order of 50% was predicted when using detector elements of about half the size of the desired spatial resolution. Instead of prescribing spatial resolution we here investigate how a square wave pattern of given detail size can be best imaged in terms of contrast, noise and dose. A contrast-to-noise quality factor Q is maximized to find the optimal detector element size g. Our findings are a potential of 70% dose reduction when using optimized flat panel detector pixel size g. This optimum lies in the order of 30% of the object detail size.
    Nuclear Science Symposium Conference Record, 2005 IEEE; 11/2005
Show more

Similar Publications