Sphingolipid Second Messengers: Tumor Suppressor Lipids

Abstract

Although lipids play a critical role in membrane formation by providing the structural backbone for cellular and organeller membranes, a functional role for lipids in cell regulation is emerging. This is clearly established for membrane glycerolipids which play critical roles in signal transduction through the generation of important metabolic products (such as diacylglycerol, inositol trisphosphate, and eicosanoids) which function as second messengers. The phosphatidylinositol (PI) cycle provides the most compelling paradigm for the involvement of membrane lipids in signal transduction. On the other hand, an analogous role for membrane sphingolipids in signal transduction has not been defined. Sphingolipids demonstrate significant structural diversity and complexity even exceeding that of glycerolipids, with multiple biologic activities and functions attributed to these molecules (1–3). The discovery of the inhibition of protein kinase C by sphingosine raised the possibility that sphingosine and other sphingolipid-derived molecules may function as second messengers (2). Indeed, studies over the last few years have begun to elucidate a sphingolipid signal transduction pathway involving the hydrolysis of sphingomyelin (SM) and the generation of ceramide, in what has been termed the sphingomyelin cycle. This chapter will highlight our current understanding of the regulation of the SM cycle, and will concentrate on more recent insight into the second messenger function of ceramide and its mechanism of action. A hypothesis suggesting a role for ceramide as a tumor suppressor lipid will be discussed.