Sphingolipid metabolism and cell growth regulation

Sphingolipids have been implicated in the regulation of cell growth, differentiation, and programmed cell death. The current paradigm for their action is that complex sphingolipids such as gangliosides interact with growth factor receptors, the extracellular matrix, and neighboring cells, whereas the backbones--sphingosine and other long-chain or "sphingoid" bases, ceramides, and sphingosine 1-phosphate--activate or inhibit protein kinases and phosphatases, ion transporters, and other regulatory machinery. Tumor necrosis factor-alpha, interleukin 1beta, and nerve growth factor, for example, induce sphingomyelin hydrolysis to ceramide. Other agonists, such as platelet-derived growth factor, trigger further hydrolysis of ceramide to sphingosine and activate sphingosine kinase to form sphingosine 1-phosphate. These metabolites either stimulate or inhibit growth and may be cytotoxic (in some cases via induction of apoptosis), depending on which products are formed (or added exogenously), the cellular levels (and possibly intracellular localization), and the cell type. In Swiss 3T3 cells, for example, sphingosine and sphingosine 1-phosphate are growth stimulatory at low concentrations via calcium mobilization from intracellular stores and activation of the mitogen-activated protein kinase (MAP kinase) pathway and transcription factors (AP-1), but are toxic at high concentrations. High levels of endogenous sphingoid bases are also produced by inhibition of ceramide synthase by fumonisins, mycotoxins produced by Fusarium moniliforme, resulting in growth stimulation or toxicity. Thus, sphingolipid metabolites appear to serve as second messengers for growth factors, cytokines, and other "physiological" agonists and, when elevated abnormally, to lead to disease.