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Nutrition and Cancer

Dietary Soy Sphingolipids Suppress Tumorigenesis and Gene Expression in 1,2-Dimethylhydrazine-Treated CF1 Mice and Apc^Min/+ Mice^1,2

Holly Symolon^*,, Eva M. Schmelz^**, Dirck L. Dillehay and Alfred H. Merrill, Jr.^,3

^* Program in Nutrition and Health Science and Department of Pathology and Division of Animal Resources, Emory University, Atlanta, GA 30322; School of Biology and the Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332; and ^** Karmanos Cancer Institute, Detroit, MI 48201

³To whom correspondence should be addressed. E-mail: Al.Merrill{at}biology.gatech.edu.

Dietary supplementation with milk sphingolipids inhibits colon tumorigenesis in CF1 mice treated with a colon carcinogen [1,2-dimethylhydrazine (DMH)] and in multiple intestinal neoplasia (Min) mice, which develop intestinal tumors spontaneously. Plant sphingolipids differ structurally from those of mammals [soy glucosylceramide (GlcCer) consists predominantly of a 4,8-sphingadiene backbone and -hydroxy-palmitic acid], which might affect their bioactivity. Soy GlcCer was added to the AIN-76A diet (which contains <0.005% sphingolipid) to investigate whether it would also suppress tumorigenesis in these mouse models. Soy GlcCer reduced colonic cell proliferation in the upper half of the crypts in mice treated with DMH by 50 and 56% (P < 0.05) at 0.025 and 0.1% of the diet (wt/wt), respectively, and reduced the number of aberrant colonic crypt foci (an early marker of colon carcinogenesis) by 38 and 52% (P < 0.05). Min mice fed diets containing 0.025 and 0.1% (wt/wt) soy GlcCer developed 22 and 37% fewer adenomas (P < 0.05), respectively. The effects of dietary sphingolipids on gene expression in the intestinal mucosal cells of Min mice were analyzed using Affymetrix GeneChip microarrays. Soy GlcCer affected the expression of 96 genes by 2-fold in a dose-dependent manner, increasing 32 and decreasing 64. Decreases in the mRNA expression of two transcription factors associated with cancer, hypoxia-induced factor 1 (HIF1) and transcription factor 4 (TCF4), were confirmed by quantitative RT-PCR. In conclusion, soy GlcCer suppressed colon tumorigenesis in two mouse models; hence, plant sphingolipids warrant further investigation as inhibitors of colon cancer. Because soy contains relatively high amounts of GlcCer, sphingolipids may partially account for the anticancer benefits attributed to soy-based foods.

KEY WORDS: • sphingolipids • soy • gene expression • colon cancer • mouse models

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