Modulation of intracellular beta-catenin localization and intestinal tumorigenesis in vivo and in vitro by sphingolipids

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)/beta -catenin regulatory system. Therefore, C57B1/ 6J(Min/+) mice wit h a truncated APC gene product were fed diets supplemented with ceramide, s phingomyelin, glucosylceramide, lactosylceramide, and ganglioside G(D3) (a composition similar in amount and type to that of dairy products) to determ ine whether tumorigenesis caused by this category of genetic defect is supp ressed. Sphingolipid feeding reduced the number of tumors in all regions of the intestine, and caused a marked redistribution of beta -catenin from a diffuse (cytosolic plus membrane) pattern to a more "normal" localization a t mainly intercellular junctions between intestinal epithelial cells. The m ajor digestion product of complex sphingolipids is sphingosine, and treatme nt of two human colon cancer cell lines in culture (SW480 and T84) with sph ingosine reduced cytosolic and nuclear beta -catenin, inhibited growth, and induced cell death. Ceramides, particularly long-chain ceramides, also had effects. Thus, dietary sphingolipids, presumably via their digestion produ cts, bypass or correct defect(s) in the APC/beta -catenin regulatory pathwa y. 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.