cell survival, and tumorigenesis. The first reported biological action of ceramide-1-phosphate was its ability to stimulate DNA synthesis and cell division. Ceramide-1-phosphate was also found to be mitogenic for both fibroblasts and macrophages. The mitogenic effect of ceramide-1-phosphate is dependent on its intracellular ability to stimulate reactive oxygen specie production in macrophages via the enzyme NADPH oxidase. This enzyme is downstream of PKC-α and cPLA(2)-α in this pathway. Another important function of ceramide-1-phophate is its promotion of cell survival. Ceramide-1-phosphate stimulates the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (PKB) pathway, a major mechanism whereby growth factors promote cell survival. It is probable that ceramide-1-phosphate blocks apoptosis by stimulating the PI3-K/PKB/NFkappaB pathway and thereby maintaining the production of antiapoptotic Bcl-X(L). Based on these and previous findings it has been proposed that the inhibition of acid sphingomyelinase and the subsequent decrease in ceramide levels would allow cell signaling through stimulation of the PI3-K/PKB pathway to promote cell survival.
