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Carcinogenesis |
Departments of Biochemistry [E. M. S., E. M. K., M. C. S., A. H. M.], Microbiology and Immunology [P. C. R.], and Pathology and Division of Animal Resources [D. L. D.], Emory University School of Medicine, Atlanta, Georgia 30322-3050, and Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201 [E. M. S., L. A. L.]
Sphingolipid consumption suppresses colon carcinogenesis, but the specific genetic defect(s) that can be bypassed by these dietary components are not known. Colon tumors often have defect(s) in the adenomatous polyposis coli (APC)/ß-catenin regulatory system. Therefore, C57Bl/6JMin/+ mice with a truncated APC gene product were fed diets supplemented with ceramide, sphingomyelin, glucosylceramide, lactosylceramide, and ganglioside GD3 (a composition similar in amount and type to that of dairy products) to determine whether tumorigenesis caused by this category of genetic defect is suppressed. Sphingolipid feeding reduced the number of tumors in all regions of the intestine, and caused a marked redistribution of ß-catenin from a diffuse (cytosolic plus membrane) pattern to a more "normal" localization at mainly intercellular junctions between intestinal epithelial cells. The major digestion product of complex sphingolipids is sphingosine, and treatment of two human colon cancer cell lines in culture (SW480 and T84) with sphingosine reduced cytosolic and nuclear ß-catenin, inhibited growth, and induced cell death. Ceramides, particularly long-chain ceramides, also had effects. Thus, dietary sphingolipids, presumably via their digestion products, bypass or correct defect(s) in the APC/ß-catenin regulatory pathway. This may be at least one mechanism whereby dietary sphingolipids inhibit colon carcinogenesis, and might have implications for dietary intervention in human familial adenomatous polyposis and colon cancer.
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