Regulation of β‐catenin and connexin‐43 expression: Targets for sphingolipids in colon cancer prevention

Abstract

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.

Sphingolipids in human ileostomy content after meals containing milk sphingomyelin

“…Consumption of sphingolipids (0.05-0.1% wt:wt in the diet as compared with 0.01-0.02% in a Western diet) was shown to counteract experimental colon cancer (11,(27)(28)(29). Sphingomyelin has also been shown to inhibit cholesterol absorption (9) and to lower plasma lipids in lipid-and cholesterol-fed apoE Leyden mice (30).…”

Clinical significance of vascular endothelial growth factor and connexin43 for predicting pancreatic cancer clinicopathologic parameters

“…At present, it is believed that vascularization and the functional disorder of gap junctional intercellular communication (GJIC) which is mediated by connexin (Cx) on cytomembrane correlate with the occurrence, development and metastasis of human tumor [1][2][3][4]. Vascular endothelial growth factor (VEGF) plays an important role in the new vascularization of tumor [5][6][7].…”

Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

“…However, in breast cancers, methylation of CpG islands appears to be important for the expression of connexon [200]. Sphingolipids have been tested in colon cancer cell lines with evidence that they suppress β-catenin and upregulate Cx43, both of which have been correlated to colon cancer [201]. In addition to their physical docking to neighboring cells, Connexins appear to modify the expression of other docking molecules, such as E-Cadherin, further inhibiting cell migration [202].…”