On the role of sphingolipids in cell survival and death.

Sphingolipids, universal components of biological membranes of all eukaryotic organisms, from yeasts to mammals, in addition of playing a structural role, also play an important part of signal transduction pathways. They participate or, also, ignite several fundamental subcellular signaling processes but, more in general, they directly contribute to key biological activities such as cell motility, growth, senescence, differentiation as well as cell fate, i.e., survival or death. The sphingolipid metabolic pathway displays an intricate network of reactions that result in the formation of multiple sphingolipids, including ceramide, and sphingosine-1-phosphate. Different sphingolipids, that have key roles in determining cell fate, can induce opposite effects: as a general rule, sphingosine-1-phosphate promotes cell survival and differentiation, whereas ceramide is known to induce apoptosis. Furthermore, together with cholesterol, sphingolipids also represent the basic lipid component of lipid rafts, cholesterol- and sphingolipid-enriched membrane microdomains directly involved in cell death and survival processes. In this review, we briefly describe the characteristics of sphingolipids and lipid membrane microdomains. In particular, we will consider the involvement of various sphingolipids per se and of lipid rafts in apoptotic pathway, both intrinsic and extrinsic, in nonapoptotic cell death, in autophagy, and in cell differentiation. In addition, their roles in the most common physiological and pathological contexts either as pathogenetic elements or as biomarkers of diseases will be considered. We would also hint how the manipulation of sphingolipid metabolism could represent a potential therapeutic target to be investigated and functionally validated especially for those diseases for which therapeutic options are limited or ineffective.