Abstract 5684: B-catenin-dependent and independent changes in gene expression induced by sphingolipids

Abstract

Abstract Dietary supplementation with sphingolipids inhibits colon tumorigenesis in carcinogen-treated CF1 mice and in multiple intestinal neoplasia (Min) mice that produce intestinal tumors spontaneously. In both cancer models the regulation of β-catenin by sphingolipid metabolites is an important early event. Stabilization and nuclear translocation of β-catenin and its interaction with T-cell factor (TCF)/lymphoid enhancer factor (LEF) play important roles to activate the transcription of genes associated with cancer development and progression. Sphingosine and ceramides, major digestion products of complex sphingolipids in the diet, down-regulate β-catenin transcriptional activity in a dose- and time-dependent manner. Our data indicate that sphingosine and ceramides suppress SW480 human colon cancer cell growth in a concentration-dependent manner. In the present study, we investigated the dependency of sphingosine- and ceramide-induced changes in gene expression on β-catenin transcriptional activity by comparing control and β-catenin siRNA treated cells. We observed changes in the expression of genes involved in signal transduction, transcription factors, cell cycle control and DNA damage repair, cell adhesion, cell invasion and metastasis, angiogenesis, and apoptosis and cell senescence. Most genes were regulated by all metabolites; however, some genes were only targeted by specific metabolites. Furthermore, only a small number of genes regulated by the sphingolipid metabolites relied completely on the activation of the β-catenin transcriptional activity. Further experiments are currently being performed to confirm the function of β-catenin on the regulation of these genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5684.