Sphingosine kinase 1 is up-regulated in colon carcinogenesis

ABSTRACT Sphingosine kinase 1 (SK1) phosphorylates sphingosine to form sphingosine 1‐phosphate (S1P), which has the ability to promote cell proliferation and survival and stimulate angiogenesis. The SK1/S1P pathway also plays a critical role in regulation of cyclooxygenase‐2 (COX‐2), a well‐established pathogenic factor in colon carcinogenesis. Therefore, we examined the expression of SK1 and COX‐2 in rat colon tumors induced by azoxymethane (AOM) and the relationship of these two proteins in normal and malignant intestinal epithelial cells. Strongly positive SK1 staining was found in 21/28 (75%) of rat colon adenocarcinomas induced by AOM, whereas no positive SK1 staining was observed in normal mucosa. The increase in SK1 and COX‐2 expression in AOM‐induced rat colon adenocarcinoma was confirmed at the level of mRNA by real‐time RT‐PCR. In addition, it was found that 1) down‐regulation of SK1 in HT‐29 human colon cancer cells by small interfering RNA (siRNA) decreases COX‐2 expression and PGE2 production; 2) overexpression of SK1 in RIE‐1 rat intestinal epithelial cells induces COX‐2 expression; and 3) S1P stimulates COX‐2 expression and PGE2 production in HT‐29 cells. These results suggest that the SK1/S1P pathway may play an important role in colon carcinogenesis, in part, by regulating COX‐2 expression and PGE2 production.