Regulation of ß-catenin and connexin-43 expression: targets for sphingolipids in colon cancer prevention

Sphingolipid metabolites are generated throughout the intestinal tract after hydrolysis of orally administered complex sphingolipids and significantly suppress colon cancer in carcinogen-treated CF1 mice. In the present study, the mechanisms of tumor suppression by dietary sphingolipids were investigated. Changes in select genes that are critical in early stages of colon cancer were analyzed in the colonic mucosa of dimethylhydrazine-treated CF1 mice fed AIN76A diet with or without 0.05% sphingomyelin. Supplementation with sphingomyelin did not significantly alter mRNA levels of most of the selected genes. However, a downregulation of ß-catenin (p=0.007) and increased protein levels of connexin-43 (p=0.017) and Bcl-2 (p=0.033) were observed in sphingomyelin-fed animals. This suggests that sphingolipids may be regulating specific post-transcriptional events to reverse aberrant expression of individual proteins. Since the dysregulation of ß-catenin metabolism and its transcriptional activity in addition to a decreased inter-cellular communication has been causally linked to the development of colon cancer while a low Bcl-2 expression is associated with a worse prognosis in colon cancer, the reversal of these early changes may be important events in the prevention of colon cancer by orally administered sphingolipids, and may provide specific molecular biomarkers for sphingolipid efficacy in vivo .