[HTML][HTML] The therapeutic potential of modulating the ceramide/sphingomyelin pathway

R Kolesnick - The Journal of clinical investigation, 2002 - Am Soc Clin Investig
R Kolesnick
The Journal of clinical investigation, 2002Am Soc Clin Investig
While ceramide has been proposed as a messenger for events as diverse as differentiation,
senescence, proliferation, and cell cycle arrest, a larger body of research has focused on its
role in apoptosis (7, 8). Evidence supporting ceramide as a message for apoptosis induction
is based on data from many cell systems and comes from several kinds of studies. First,
agonist-and stress-induced increases in ceramide levels precede biochemical and
morphologic manifestations of apoptosis in many systems. Second, increasing cellular …
While ceramide has been proposed as a messenger for events as diverse as differentiation, senescence, proliferation, and cell cycle arrest, a larger body of research has focused on its role in apoptosis (7, 8). Evidence supporting ceramide as a message for apoptosis induction is based on data from many cell systems and comes from several kinds of studies. First, agonist-and stress-induced increases in ceramide levels precede biochemical and morphologic manifestations of apoptosis in many systems. Second, increasing cellular ceramide by addition of natural ceramide, exogenous SMase, or pharmacologic agents that interfere with enzymes of ceramide metabolism mimics effects of stress on apoptosis induction. Third, genetic models, including Niemann-Pick Disease cells, Asmase–/–mice, and Glucosylceramide synthase–/–mice, manifest the predicted abnormalities in stress responses from the biochemical and cell biologic studies. In view of the fact that other sphingolipid metabolites (except perhaps sphingoid bases and GD3 in selected cells) are not cytotoxic (7, 8), it thus appears that ceramide per se is necessary and likely sufficient for some forms of cell stress–associated apoptosis. Interestingly, ceramide may serve as a stress response signal even in Saccharomyces cerevisiae, as yeast mutants incapable of rapid de novo synthesis of this sphingolipid class fail to adapt and to regrow at elevated temperatures, and instead undergo growth arrest. This defect is bypassed by exogenous sphingolipid, indicating an obligate requirement for sphingolipids for this response. Thus, ceramide/sphingolipid signaling may constitute a programmed stress response that predates apoptosis evolutionarily. One proposal that may help explain how ceramide serves these diverse functions is that of the “S1P Rheostat”(22). Spiegel and coworkers based this proposal on the observation that ceramide and its metabolite S1P often have opposing effects on biologic outcome. While ceramide is often antiproliferative and proapoptotic, S1P has been implicated as a second messenger in cellular proliferation and survival (23), and in protection against ceramide-mediated apoptosis (22). Thus, it has been suggested that the balance between these two sphingolipid messages may be an important factor determining survival or death of mammalian cells (23). As sphingosine levels in mammalian cells are often one to two orders of magnitude lower than those of ceramide, the generation of substantial amounts of S1P requires additional sphingosine production. Typically, S1P is produced by the coordinate activation of SMase to generate ceramide, ceramidase to free up sphingosine, and sphingosine kinase (24). In fact, activation of ceramidase may be so robust in some cells that the ceramide levels never rise substantially, indicating that SM has been converted stoichiometrically to sphingosine. For this reason, activation of the SM pathway can never be ruled out by the failure to detect ceramide increases, unless measurements of SM, sphingosine, and S1P levels are also available. The recent discovery of a set of cell surface S1P receptors, the EDG proteins, has further complicated the interpretation of S1P dynamics (24). It is not yet clear to what extent S1P functions by ligating these receptors, rather than by acting as an intracellular signal. The available data suggest that, by either mode, it antagonizes ceramide-mediated biologic responses. Other metabolic pathways may also contribute to the diverse action of ceramide in different cellular systems. In general, the ceramide backbone of sphingolipids is generated in the endoplasmic reticulum, and the head groups are added …
The Journal of Clinical Investigation