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:
1) Although it is known that selenium (Se) may reduce colon cancer risk, the anticancer efficacy of Se against obesity/high-fat diet related colon cancer remains to be elucidated. We hypothesized that CH3SeH, an in vivo Se metabolite pool, reduces the obesity/high fat diet related colon cancer. To determine the extent to which Se reduces obesity/high fat diet related colon cancer, we established an oral daily Se ingestion (in vivo) method in C57/BL mice fed with low/high fat diets. Completed a study on the inhibitory effect of CH3SeH on both colon cancer proliferation (in vitro), tumor growth potential in a colon cancer mouse model (in vivo), and we now are working on molecular/biochemical analysis. In addition, we are establishing chemical (the azoxymethane-AOM) induced colon cancer mouse model which will allow us to study diet and colon cancer risk including both tumor initial and development stages. 2) Butyrate, produced in the colon by the bacterial fermentation of carbohydrate, induces cell growth inhibition in colonic epithelial cells, which may contribute to protection against colon cancer. On the other hand, the cell growth inhibition induced by bile acid deoxycholic acid (DCA) may cause compensatory hyperproliferation of colonic epithelial cells and consequently increase colon cancer risk. We hypothesized that butyrate and DCA may employ different molecular pathways to inhibit cell proliferation. To determine the cellular basis of this opposite effect, we examined the effect of prolonged exposure of butyrate and deoxycholic acid (DCA) on colonic cell proliferation and its related signaling pathways, and found that both butyrate and DCA inhibit colon cell proliferation, each modulates cell cycle and apoptosis via the distinct cellular signaling targets. 3) The roles of selenium in secondary cancer prevention remain largely unexplored. We hypothesized that selenium reduces malignant spread. We completed an animal study that investigated the interaction of selenium and high-fat feeding on secondary tumorigenesis. Furthermore, we complete animal feeding of experiments (1) that assessed the interaction of plasminogen activator inhibitor-1 deficiency and high-fat feeding on malignant spread and (2) that determined the restricted feeding of a high-fat diet on adipogenesis; data generated will be used for designing further studies on selenium and high-fat diet on secondary tumorigenesis. 4) Changes in dietary practice and an increase in physical activity may reduce the risk of obesity. We hypothesized that soy consumption and moderate physical activity reduce the risk of obesity. We completed a 2x2x2 study that assessed interactions of soy protein supplementation and voluntary running on adiposity in high-fat diet-fed mice and changes in related inflammatory and angiogenic markers and demonstrated both soy protein and voluntary running reduced adiposity and related inflammation and the latter, not the former, was through an action of weight reduction. Our results indicate the usefulness of both soy protein and physical activity in weight management and reducing the risk of obesity.
Jackson, M.I., Cao, J.J., Zeng, H., Uthus, E.O., Combs, G.F. 2012. S-Adenosylmethionine-dependent protein methylation Is required for expression of selenoprotein P and gluconeogenic enzymes in HepG2 human hepatocytes. Journal of Biological Chemistry. 287(43):36455-36464.