1a. Objectives (from AD-416)
Determine the dietary modulation of obesity-related cancer by selenium. Specific objectives include 1) Characterize interactions of energy imbalance and dietary Se status on obesity-promoted carcinogenesis; 2) Elucidate the relationship of body mass index (BMI) and features of Se metabolism in selenoprotein genotypes differing in cancer risk.
1b. Approach (from AD-416)
This project will determine the extent to which Se counteracts the carcinogenic effects of obesity. It will do so by elucidating the effects of Se status on obesity-promoted mechanisms of carcinogenesis, and the relationships of BMI and Se metabolism among individuals of two genotypes known to differ in cancer risk. Two forms of dietary Se will be used: i) SeMet, the dominant form of Se in foods; ii) precursors of CH3SeH - CH3SeCys (catabolyzed to CH3SeH in the cell), the methylseleninic acid (MSeA) (reduced to CH3SeH in the cell), and the combination of SeMet + recombinant methionase (produces CH3SeH). The project utilizes the complementary expertise of the research team in molecular/cell biology and cell signaling (Zeng), experimental tumorigenesis (Yan, Zeng), human Se metabolism (Combs), and chemistry/ biochemistry (Jackson, Combs). The collaborative nature of the project is evident in the CH3SeH metabolism/action theme that connects the two objectives. This research builds on in-depth expertise and existing collaborations to investigate a highly relevant problem hitherto not addressed. The Grand Forks Human Nutrition Research Center provides this team of investigators with an experienced professional infrastructure for the efficient recruitment and management of human subjects and the controlled use of animal and cell models.
3. Progress Report
To determine the extent to which Selenium reduces/counteracts the effects of obesity related signaling in colon cancer tumorigenesis, we established of a colon xenograft cancer mouse model, and are examining the inhibitory effect of CH3SeH on tumor growth potential in these mice in the context of obesity. Completed the methylation analysis of genomic DNA and tumor suppressor genes in rats fed with different selenium doses. To determine the leptin-sensitive colon cells, and its tumor suppressor gene expression (e.g. p53), we identified two good cancer cell lines to work with. Completed animal feeding and a few initiated assays that examined the effect of Selenium intake and high fat diet on inflammatory response, immunity and cancer risk. Completed animal feeding and initiated assays and analysis of experiments that investigated dietary supplementation with selenium and secondary cancer development. Preliminary results showed that methylseleninic acid reduced secondary tumor development through its inhibition of urokinase plasminogen activator system. To determine the extent to which Selenium status is inversely associated with risk factors of obesity, we completed our correlation analysis of Selenium status and biomarkers related to obesity-promoted cancer (BMI, methylation status). We also are finalizing the design and IRB submission of recruiting for cross sectional kinetic Selenium studies in humans. To determine the extent to which methylation status, which is disrupted in obesity and linked to cancer risk, influences Selenium metabolism, we have initiated and concluded a study in the rat model utilizing a model for decreased systemic methylation capacity. We completed sample collection, and the majority of data analysis, and are in the process of producing a manuscript for publication from this work. Selenium inhibited secondary tumorigenesis. Although it has been well documented Selenium's anticancer property, the extent to which Selenium inhibited secondary tumorigenesis remains to be characterized. We completed animal feeding of experiments and initiated assays and analysis. Preliminary results showed that methylseleninic acid reduced secondary tumorigenesis, and this effect was related to the inhibition of urokinase plasminogen activator system, suggesting that methylseleninic acid may be a useful adjuvant in secondary cancer prevention. Interaction of soy protein and moderate physical activity on diet-induced obesity in mice. The diet and physical activity are two major factors for combating obesity. We completed animal feeding and initiated analysis. Preliminary results showed that soy protein or voluntary running reduced high-fat diet-induced obesity and expression of related inflammatory and angiogenic cytokines, and the soy and running interactions were observed in some of those measurements. Results from this study demonstrated benefits of soy and physical activity in reducing the risk of obesity, and also they are useful in designing future studies on additive or synergetic effects of soy, physical activity, and other dietary means (e.g. selenium) on secondary tumorigenesis.
Wu, M., Huang, H., Zhang, W., Kannan, S.H., Weaver, A., Mckibben, M., Herington, D., Zeng, H., Gao, H. 2011. Host DNA repair proteins in response to Pseudomonas aeruginosa in lung epitehlial cells and in mice. Infection and Immunity. 79(1):75-87.