Abstract 2875: Regulation of gene expression by sphingosine in a mouse cell model of ovarian cancer progression

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Approximately 90% of ovarian cancers are derived from the surface epithelium of the ovary. To study and further understand the early events that lead to epithelial ovarian cancer, we previously developed the syngeneic mouse ovarian surface epithelial (MOSE) model; MOSE cells have undergone spontaneous transformation in cell culture and were categorized into distinct stages by their phenotype, with early passages (MOSE-E) representing a pre-neoplastic, non-tumorigenic phenotype to late passages (MOSE-L) that demonstrate a highly aggressive malignant phenotype both in vitro and in vivo. Sphingosine, a bioactive metabolite of complex sphingolipids, has been shown to have chemopreventive properties in cancer, including colon and ovarian. In these studies we have investigated the hypothesis that sphingosine can prevent or reverse the aberrant gene expression in MOSE-L cells. Using a complete mouse genome microarray, we have identified 1412 genes that were significantly changed in the late malignant MOSE-L versus non-tumorigenic MOSE-E cells. Upon treatment of MOSE-L cells with non-toxic concentrations of sphingosine, microarray analysis revealed the down-regulation of 172 of 701 upregulated genes and up-regulation of 176 of 711 down-regulated genes in MOSE-L cells. Gene ontology analyses showed that these genes were overrepresented in specific categories with up-regulated genes involved in lipid and steroid metabolism, ER, and innate immune response while down regulated genes are involved in cell cycle, cytoskeleton and its regulation, and chromosome stability. A comparison of upregulated genes in MOSE-L cells treated with 5’-azaDC and sphingosine identified genes that are potentially epigenetically silenced by promoter methylation as cells transition from pre-neoplastic to malignant. Also, in addition to changes in gene expression, sphingosine reversed aberrant cytoskeleton organization. Taken together, this indicates that sphingosine acts as a chemopreventive agent by regulating multiple pathways including gene expression. 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 2875.