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 Se reduces a high fat diet related colon cancer, we established an oral daily Se ingestion method in C57/BL mice fed with low/high fat diets. A study was completed on the inhibitory effect of CH3SeH on both colon cancer proliferation (in vitro) and tumor growth potential in a colon cancer mouse model. We now are working on molecular/biochemical analyses. To determine the connection between gut microfloral and inflammation status, we have been simultaneously examining the effect of the consumption of a high fat diet on (a) the inflammatory process including colon cell proliferation, cytokine expression, nonalcoholic fatty liver disease; and (b) gut microfloral status in both cell culture and mouse models. We now are preparing a manuscript. The roles of selenium in secondary cancer prevention remain largely unexplored. We hypothesized that selenium reduces metastasis. We completed animal feeding experiments that 1) assessed the interaction of selenium and diet-induced obesity on spread of malignancy; and 2) compared 4 different selenium compounds on breast cancer metastasis in mice, and we initiated data analysis for these experiments. Physical exercise and dietary modification may reduce the risk of obesity. We hypothesized that exercise and soy protein may have a synergistic effect, and completed an animal feeding experiment that assessed interactions of soy protein and voluntary running on diet-induced obesity and changes in related inflammatory and angiogenic markers in mice. Analyses of our earlier work have suggested that Se supplementation may increase risk of type 2 diabetes. We decided to test this using a large cohort study because a trial to test this hypothesis is unethical. Completed the design of that study (involving 500 free-living human subjects) and are currently requesting IRB approval. Its specific objective is to determine the relationship between glycemia, adiposity and Se status. We have observed that apparently healthy, obese (BMI>30) individuals have sub-optimal expression of Se transport protein, SEPP1. We hypothesized that impaired hepatic methylation capacity, common in obesity, may alter metabolism of Se. We are testing these hypotheses in two ways: a) determining the pools of Se metabolites that require methylation which includes low molecular weight Se metabolites. b) Determining the effects of impaired hepatic methylation capacity on the regulation of Se-containing proteins. The results of these studies demonstrated that compromised methylation capacity affects the metabolism of Se metabolites thought to be anti-carcinogenic. We are preparing two manuscripts to a high-impact journal.
1. Selenium (Se) metabolites reduce a high fat diet related colon cancer. To address the question whether Se reduces a high fat diet related colon cancer, ARS researchers in Grand Forks, ND, examined the effect of Se on tumor growth potential in a colon cancer mouse model. Our data demonstrated, for the first time, that Se (CH3SeH) reduced both colon cancer proliferation (in vitro) and tumor growth potential (in vivo) in a colon cancer mouse model with a high fat diet; the Se-modulation of p53 tumor suppressor pathway played a key role in this anticancer action. These findings provide new insights into the mechanistic process of Se anticancer property, which is the scientific basis for using Se to prevent a high fat diet related colon cancer.
2. Selenium (Se) reduces metastasis. Metastasis is the most devastating aspect of cancer, and its occurrence directly affects the survival and quality life of cancer survivors. ARS researchers in Grand Forks, ND, used a mouse cancer model and demonstrated that dietary supplementation with methylseleninic acid (an active Se form) reduces malignant spread of cancer cells in mice, and this reduction is associated with its inhibition of the plasminogen activator system and angiogenesis. These results indicate that Se may be a useful adjuvant in secondary cancer prevention, and its possible application warrants further investigation.
3. Curcumin enhances metastatic growth in mice. Metastasis directly affects the survival and quality life of cancer survivors. ARS researchers in Grand Forks, ND, used a mouse cancer model and demonstrated that dietary supplementation with curcumin, a component of the spice turmeric, enhances metastatic growth in mice. This enhancement is accompanied with increases in plasma levels of angiogenic factors and inflammatory cytokines. The role of curcumin in the development and growth of malignancies with rapid progression, including metastasis, warrants further investigation.
4. Voluntary exercise improves adiposity in young adult mice. Obesity among children and adolescents continues to be a public health concern in the U.S. ARS researchers in Grand Forks, ND, demonstrated that long-term voluntary running improves diet-induced adiposity in young adult mice, which is accompanied with reduction in plasma levels of insulin, adipokines and inflammatory cytokines. These results indicate that voluntary running reduces diet-induced obesity and pro-inflammation and that young mice may be a useful model of their human age equivalents in studying moderate physical exercise and obesity and obesity-related diseases.
5. The metabolism of dietary selenium (Se) forms in healthy adults. Metabolites of dietary selenium are known to decrease carcinogenesis. ARS researchers in Grand Forks, ND, used pharmacokinetic approaches to characterize the metabolism of two major dietary forms of Se, selenomethionine and selenite. Human volunteers were given nutritional doses of two forms of dietary Se each labeled with a different marker. The marker allowed the measurement of the uptake and turnover of each Se species under normal conditions. These data provide new insights on Se metabolism, which provides the scientific basis for making dietary Se intake guideline.
6. Selenoprotein P expression is reduced when the capacity for methylation is reduced, as occurs in many obese individuals. Reduced expression of selenoprotein P, which transports selenium through the body, reduces the health functions of selenium. ARS researchers at the Grand Forks Human Nutrition Research Center discovered that the synthesis of selenoprotein P in human liver cells depends on the methylation of protein factors that regulate its gene expression. These proteins are also involved in glycemic control, loss of which occurs in type 2 diabetes. This new information shows that selenium status is related to risk to obesity-related disease.Combs, G.F., Jackson, M.I., Watts, J.J., Johnson, L.K., Zeng, H., Idso, J.P., Schomburg, L., Hoeg, A., Hoefig, C.S., Chiang, E.C., Waters, D.J., Tsuji, P.A., Davis, C.D., Milner, J.A. 2012. Differential responses to selenomethioinine supplementation by sex and genotype in healthy adults. British Journal of Nutrition. 107:1514-1525.