Nutrition & Food Science
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Item Selenium Supranutrition: Are the Potential Benefits of Chemoprevention Outweighed by the Promotion of Diabetes and Insulin Resistance?(MDPI, 2013-04-19) Rocourt, Caroline R. B.; Cheng, Wen-HsingSelenium was considered a toxin until 1957, when this mineral was shown to be essential in the prevention of necrotic liver damage in rats. The hypothesis of selenium chemoprevention is principally formulated by the observations that cancer incidence is inversely associated with selenium status. However, recent clinical and epidemiological studies demonstrate a role for some selenoproteins in exacerbating or promoting other disease states, specifically type 2 diabetes, although other data support a role of selenium in stimulating insulin sensitivity. Therefore, it is clear that our understanding in the role of selenium in glucose metabolism and chemoprevention is inadequate and incomplete. Research exploring the role of selenium in individual healthcare is of upmost importance and possibly will help explain how selenium is a double-edged sword in the pathologies of chronic diseases.Item Methylseleninic Acid Sensitizes Notch 3-activated OVCA429 Ovarian Cancer Cells to Carboplatin(2012) Tzeng, Tiffany Jean; Cheng, Wen-Hsing; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Ovarian cancer is the deadliest of gynecologic cancers and is usually diagnosed at advanced stage due to invalidated screening test. Although carboplatin has been used for treating ovarian cancer for years, high-grade serous ovarian cancer expressing a constitutively active form of the intracellular domain of Notch 3 develops resistance to this platinum-containing drug. Thus, finding a novel treatment or therapeutic targets are necessary. Here we test the hypothesis that the combinational treatment of methylseleninic acid (MSeA) and carboplatin, two chemicals displaying overlapping effect on DNA damage response, may target Notch 3 for improved efficacy on ovarian cancer treatment. The OVCA429/NICD3 cells expressing an activated form of Notch 3 were resistant to carboplatin, but co-treatment with MSeA synergistically sensitized the cell to an extent similar of that in OVCA429/pCEG control cells. The synergistic effect can be suppressed by the presence of a hydrogen peroxide scavenger N-acetyl cysteine (NAC) and kinase inhibitors of ATM and DNA-PKcs. In summary, MSeA and carboplatin synergistically sensitize OVCA429/NICD3 cells in a pathway involves oxidative stress, ATM and DNA-PKcs, suggesting a new strategy to improve the efficacy of carboplatin treatment for high-grade ovarian cancer.Item Selenium compounds activate early barriers of tumorigenesis(2011) WU, MIN; Cheng, Wen-Hsing; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Selenium chemoprevention by apoptosis has been well studied, but it is not clear whether selenium can activate early barriers of tumorigenesis, namely senescence and DNA damage response. To test this hypothesis, we treated normal and cancerous cells with a gradient concentration of sodium selenite, methylseleninic acid and methylselenocysteine for 48 h, followed by a recovery of 1-7 days. Here we show that selenium compounds at doses of ≤LD50 can induce cellular senescence, as evidenced by the expression of senescence-associated β-galactosidase and 5-bromo-2-deoxyuridine incorporation, in normal but not cancerous cells. In response to clastogens, the ataxia telangiectasia mutated (ATM) protein is rapidly activated, which in turn initiates a cascade of DNA damage response. We found that the ATM pathway is activated by the selenium compounds, and the kinase activity is required for the selenium induced senescence response. Pretreatment of the MRC-5 non-cancerous cells with the antioxidant N-acetylcysteine or 2,2,6,6-tetramethylpiperidine-1-oxyl suppresses the selenium induced ATM activation and senescence. Taken together, the results suggest a novel role of selenium in the activation of early tumorigenesis barriers specific in non-cancerous cells, whereby selenium induces an ATM-dependent senescence response that depends on reactive oxygen species. The tumor suppressor p53 is a substrate of the ATM kinase and plays an important role in senescence. To determine mechanism by which selenium induces the ATM-dependent senescence, we employed shRNA knockdown approach and other DNA damage assays to determine the role of p53 in the senescence response. Results from senescence-associated expression of β-galactosidase assay indicate that p53 shRNA MRC-5 cells did not show senescent phenotype with a series of concentrations of methylseleninic acid (0-10 μM) after 7-day recovery. However, loss of p53 renders MRC-5 cells more resistant to MSeA treatment and increased its genomic instability. We also observe that MSeA can cause increased irreversible G2/M arrest in scramble MRC-5 cells but treated p53 shRNA MRC-5 can recover back to non-treated status after 7-day recovery. Taken together, p53 is involved in the ATM-dependent senescence in the response of MRC-5 normal cells to selenium compounds.Item EFFECT OF DIETARY SELENIUM STATUS ON T CELL IMMUNITY AND CANCER XENOGRAFT IN NUDE MICE(2010) Holmstrom, Alexandra; Cheng, Wen-Hsing; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Selenium (Se) is known to regulate carcinogenesis and immunity at nutritional and supranutritional levels. Because the immune system provides one of the main body defenses against cancer, we asked whether T cell immunity can modulate selenium chemoprevention. Homozygous NU/J nude mice were fed selenium-deficient, torula yeast basal diet alone or supplemented with 0.15 or 1 mg Se/kg for 8 months in Experiment 1 and for 11 weeks in Experiment 2. Mice were inoculated with PC-3 prostate cancer cells followed by a 7-week tumor development. Peripheral T cells were analyzed at baseline, day 9, 19, 34 and 47 by flow cytometry. Tumor development in adult nude mice (Experiment 1) was suppressed whereas in young nude mice (Experiment 2) was promoted by feeding a high selenium diet. Dietary selenium deficiency does not affect tumor weight. After xenograft, dietary selenium status does not affect levels of CD4 and CD8 T cells in adult nude mice in Experiment 1, while high selenium resulted in significant decrease in CD4 T cells in young nude mice in Experiment 2. Taken together, there is an opposing role of excessive selenium on tumor xenograft development in adult and young nude mice carrying differential T cell profiles.Item HOW SELENIUM MODIFIES CROSS-TALK BETWEEN THE PIKK FAMILY AND INSIGHTS ON THE REGULATION OF DNA-PKcs(2009) Rocourt, Caroline; Cheng, Wen-Hsing; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)We recently found that ATM is required for a selenium-induced senescence response in non-cancerous cells. We hypothesize the selenium-induced DNA damage response modifies ATM and DNA-PKcs cross-talk. Phospho-specific antibodies against ATM and DNA-PKcs were used to follow the phosphorylation events after selenium treatment in normal human cells and two human cancer cell lines. Results from immunofluorescence analysis showed that selenium treatment induces hyperphosphorylation of DNA-PKcs at T2647 and S2056 in non-cancerous MRC-5 cells but not in U-2 OS cancer cells. Further studies in MRC-5 cells treated with an ATM kinase inhibitor, KU 55933, showed attenuation of the selenium-induced DNA-PKcs phosphorylation at both foci, whereas pre-treatment with a DNA-PKcs kinase inhibitor, NU 7026, does not prevent ATM phosphorylation at S1981, an event leading to ATM pathway activation. These results give evidence that DNA-PKcs and ATM have a cooperative role in the DNA damage response pathway.