Abstract B80: Role for sphingosine kinase 1 in colon carcinogenesis

Colorectal cancer remains the 2^nd leading cause of cancer‐related deaths in the US despite recent advances in screening and therapeutic technology. Recent studies suggest that bioactive sphingolipids are key in regulating the arachidonic acid cascade of inflammation, which is significant in colon cancer pathogenesis. Sphingolipid metabolites such as ceramide, sphingosine, and sphingosine‐1‐phosphate (S1P) are a new class of lipid messengers that regulate cell functions. Sphingosine kinase 1 (SphK1), phosphorylates sphingosine to form S1P, is a critical regulator of sphingolipid‐mediated functions, as it not only produces the pro‐growth, anti‐apoptotic messenger S1P, but also decreases pro‐apoptotic ceramide and sphingosine. Our previous studies implicated the SphK1/S1P pathway in induction of the arachidonic acid cascade, a major inflammatory pathway involved in colon carcinogenesis (FASEB J., 20: 386–388, 2006). Then, we investigated whether the SphK1/S1P pathway is necessary for mediating carcinogenesis in vivo. We report that 89% (n=47) of human colon cancer samples stained positively for SphK1 whereas normal colon mucosa had negative or weak staining. Adenomas had higher SphK1 expression versus normal mucosa, and metastatic colon cancers had higher SphK1 expression than those without metastases. In an azoxymethane (AOM) murine model of colon cancer, SphK1 and S1P were significantly elevated in colon cancer tissues compared to normal mucosa. Moreover, blood levels of S1P were higher in mice with colon cancers than in those without cancers. Importantly, SphK1^−/− mice subjected to AOM had significantly less aberrant crypt foci (ACF) formation and significantly reduced colon cancer development. These results suggest that the SphK1/S1P pathway contributes to colon carcinogenesis and that inhibition of this pathway is a potential target for chemoprevention. In this paper, we discuss more details of the role of the SphK1/S1P pathway in colon carcinogenesis and the effects of SphK1 inhibition in cardiovascular risk.

Citation Information: Cancer Prev Res 2010;3(1 Suppl):B80.