This project studies novel mechanisms by which dietary factors, using soy protein isolate as the nutritional paradigm, inhibit colon cancers of the rat and mouse (and by inference human). The Central Hypothesis under study posits that dietary soy protein isolate reduces circulating insulin levels and as a consequence, colonic expression of lipogenic enzymes, which in turn confers reduced proliferation and increased apoptosis during colon tumor initiation and progression. Sprague-Dawley rats will be fed high fat diets to induce obesity and hyperinsulinemia. Diets will contain equal amounts of casein (control protein) or soy protein isolate (SPI). These dietary proteins elicited significant differences in intestinal tumor indices after administration of the chemical carcinogen, azoxymethane (AOM). SPI suppressed: a) numbers of aberrant crypt foci (ACF;intermediate end-point biomarker of colon adenomas/carcinomas), b) incidence of colon tumors, c) systemic insulin levels, and d) expression of lipogenic enzyme genes in colon (both prior to and during tumorigenesis). Soy protein, when fed only during pregnancy, influenced the outcome of AOM-induced tumorigenesis in the progeny as later adults (""""""""nutritional programming"""""""" of colon cancer). Thus, there is support for linkages of dietary protein type, metabolic regulation of lipid synthetic enzyme genes, and colon cancer.
Three Specific Aims will examine these proposed linkages by elucidating the inhibitory actions of dietary SPI on initiation of colon tumorigenesis in the high fat-fed, obese rat;examining the inhibitory actions of dietary SPI on colon tumor progression in the high fat-fed rat and mouse;and investigating mechanisms of obesity-induced fetal programming of colon tumorigenesis. Emphasis in all three Aims will be on lipogenic enzyme genes as downstream pro-proliferative and anti-apoptotic targets of insulin and thyroxine, in obese states. Long-term goals are to utilize proteins/peptides and non-protein bio-active factors present in soy protein isolates, and the targeting of downstream lipogenic enzyme genes/pathways, to augment human colo-rectal cancer- and obesity-prevention strategies. These studies have strong translational significance for improving the health and quality of life of the overweight/obese population at risk for or afflicted with colo-rectal cancer.

Public Health Relevance

The clinical significance of the project stems from the potential identification of colon cancer-preventive dietary factors in soy. Also highly relevant and innovative is the proposed testing of new treatment paradigms for colo-rectal cancer that involve specific combinations of dietary proteins and drugs. In the long-term, results from these studies may help in the design of foods and drugs that have colon cancer-preventive actions, with positive consequences on health and quality of life for those at risk or afflicted with this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136493-04
Application #
8386941
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Emenaker, Nancy J
Project Start
2009-12-15
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$274,339
Indirect Cost
$85,140
Name
University of Arkansas for Medical Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Heard, Melissa E; Melnyk, Stepan B; Simmen, Frank A et al. (2016) High-Fat Diet Promotion of Endometriosis in an Immunocompetent Mouse Model is Associated With Altered Peripheral and Ectopic Lesion Redox and Inflammatory Status. Endocrinology 157:2870-82
Simmen, Rosalia C M; Kelley, Angela S (2016) Reversal of fortune: estrogen receptor-β in endometriosis. J Mol Endocrinol 57:F23-7
Montales, Maria Theresa E; Melnyk, Stepan B; Liu, Shi J et al. (2016) Metabolic history impacts mammary tumor epithelial hierarchy and early drug response in mice. Endocr Relat Cancer 23:677-90
Brown, Adam R; Simmen, Rosalia C M; Raj, Vinay R et al. (2015) Krüppel-like factor 9 (KLF9) prevents colorectal cancer through inhibition of interferon-related signaling. Carcinogenesis 36:946-55
Montales, Maria Theresa E; Simmen, Rosalia C M; Ferreira, Ederlan S et al. (2015) Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells. Genes Nutr 10:49
Simmen, Rosalia C M; Heard, Melissa E; Simmen, Angela M et al. (2015) The Krüppel-like factors in female reproductive system pathologies. J Mol Endocrinol 54:R89-R101
Montales, Maria Theresa E; Melnyk, Stepan B; Simmen, Frank A et al. (2014) Maternal metabolic perturbations elicited by high-fat diet promote Wnt-1-induced mammary tumor risk in adult female offspring via long-term effects on mammary and systemic phenotypes. Carcinogenesis 35:2102-12
Al-Dwairi, Ahmed; Brown, Adam R; Pabona, John Mark P et al. (2014) Enhanced gastrointestinal expression of cytosolic malic enzyme (ME1) induces intestinal and liver lipogenic gene expression and intestinal cell proliferation in mice. PLoS One 9:e113058
Brown, Adam R; Simmen, Rosalia C M; Simmen, Frank A (2013) The role of thyroid hormone signaling in the prevention of digestive system cancers. Int J Mol Sci 14:16240-57
Rahal, Omar M; Pabona, John Mark P; Kelly, Thomas et al. (2013) Suppression of Wnt1-induced mammary tumor growth and lower serum insulin in offspring exposed to maternal blueberry diet suggest early dietary influence on developmental programming. Carcinogenesis 34:464-74

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