Sphingosine kinase 1 mediates colon carcinogenesis

Accumulating evidence suggests that sphingolipids may play a pivotal role for colon carcinogenesis. Sphingosine kinase 1 (SphK1), an inducible form of enzymes to phosphorylate sphingosine to sphingosine 1-phosphate (S1P), is a key regulator of sphingolipid metabolism since S1P promotes cell proliferation and survival, and regulates angiogenesis, whereas sphingosine and ceramide inhibit cell proliferation and stimulate apoptosis. Our previous data indicated that 1) SphK1 is overexpressed in colon cancer in human and rodents; 2) SphK1/S1P pathway regulates cyclooxygenase 2 (COX-2) and its product, prostaglandin E2 (PGE2), most studied molecules for colon carcinogenesis in human colon cancer cells; 3) inhibition of SphK1 significantly reduces rodent colon carcinogenesis; and 4) inhibition of SphK1 is safer in hypertension than COX-2 inhibitors since SphK1 inhibition does not worse hypertension induced by angiotensin II in rodents while a COX-2 inhibitor does. We would like to summarize and discuss these data and new data that SphK1 overexpression enhances colon carcinogenesis and SphK1 inhibitors inhibit colon carcinogenesis. We would like to discuss future plans and the possible strategy for colon cancer chemoprevention using SphK1 inhibitors in this presentation.