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.
1. Gut bacteria play a critical role in obesity related fatty liver disease. High-fat diets produce obesity and are linked to the development of nonalcoholic fatty liver disease. ARS researchers in Grand Forks, ND, determined the correlation of fatty liver and predominant gut bacteria in a diet-induced obesity mouse model. These data demonstrated marked changes in increase of gut bacteria with high-fat feeding that were associated with the development of fatty liver. These findings provide new insights into the mechanistic process of diet, obesity and fatty liver.
2. Piperlongumine (PPLGM) compounds activates cell growth related pathway in fighting cancer. PPLGM is a bioactive compound isolated from long peppers that may be used against cancer. To test the hypothesis that PPLGM may work through the cell proliferation pathway, ARS researchers in Grand Forks, ND, identified the contribution of the key cell proliferation pathway in PPLGM-mediated colon cancer cell death. These findings provide new insights into the mechanistic process of PPLGM anticancer property, which is the scientific basis for using PPLGM to prevent colon cancer.
3. Dietary curcumin reduces bone structure. Improvement in survival rate and quality life of cancer patients is the key determining the success of cancer prevention. ARS researchers in Grand Forks, ND, demonstrated that dietary curcumin supplementation reduced bone structure in both non-tumor-bearing and tumor-bearing mice. Curcumin has been investigated as a chemopreventive agent in clinical trials. These results indicate the possibility of combined effect of cancer-induced osteolysis and curcumin-stimulated bone loss in cancer patients using curcumin. Thus, the assessment of bone structure changes should be considered for those patients who participate in curcumin clinical trials to determine its effects on skeletal health.
4. Selenium (Se) transporter, a selenoprotein, is involved in type 2 diabetes / cancer risk, and the data indicate that Se status is related to risk to obesity-related disease. Cellular methylation, a protein medication process, enables expression of glucose formation enzymes and metabolism of the nutrient Se. To test the hypothesis that methylation status may alter the expression of Se-transporter, ARS researchers in Grand Forks, ND, examined/demonstrated that disruption of methylation pathway reduced Se-transporter (SEPP1 protein) expression. This effect is at the level of RNA but not protein. These findings provide the scientific basis of Se intake and potential molecular targets to prevent type 2 diabetes/cancer risk. [Neither dietary selenium nor selenoprotein status affect the incidence of hepatocarcinogenesis driven by TGFa, but their deficiency induces widespread pyogranuloma formation.
5. Demonstrated that genotype influences selenium (Se) metabolism associated with cancer risk. To test the hypothesis that certain selenoprotein genotypes may affect the rate of Se metabolism, ARS researchers in Grand Forks, ND, examined the extent to which selenoprotein genotypes contribute to interindividual variation in their expression and activity. Our results showed that individuals with certain genotypes at glutathione peroxidase (GPX1) regulate Se metabolism/level which is associated with cancer risk. These studies indicate genetic determinants associated with cancer risk also affect Se status and metabolism – the first evidence of an association of aberrant Se metabolism and cancer risk, providing the metabolic basis for the relationship of obesity and Se metabolism.
6. Demonstrated presence of selenium (Se)-metabolites in animal/human plasma and urine. It has been hypothesized that non-protein fractions such as low molecular weight Se metabolites play a critical role in anticancer action, but to detect/measure these metabolites is a big challenge. ARS researchers in Grand Forks, ND, have optimized the method to eliminate protein-bound Se from samples by organic solvent precipitation and filtration; developed sensitive detection methods for Se-metabolites. These novel analytical methods/ approached will be widely used in future Se research and other related nutritional studies.
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.