Cancer Treatment Strategies Targeting Sphingolipid Metabolism

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Abstract

Ceramide and sphingosine-1-phosphate are related sphingolipid metabolites that can be generated through a de novo biosynthetic route or derived from the recycling of membrane sphingomyelin. Both these lipids regulate cellular responses to stress, with generally opposing effects. Sphingosine-1-phosphate functions as a growth and survival factor, acting as a ligand for a family of G protein-coupled receptors, whereas ceramide activates intrinsic and extrinsic apoptotic pathways through receptor-independent mechanisms. A growing body of evidence has implicated ceramide, sphingosine-1-phosphate and the genes involved in their synthesis, catabolism and signaling in various aspects of oncogenesis, cancer progression and drug- and radiation resistance. This may be explained in part by the finding that both lipids impinge upon the PI3K/AKT pathway, which represses apoptosis and autophagy. In addition, sphingolipids influence cell cycle progression, telomerase function, cell migration and stem cell biology. Considering the central role of ceramide in mediating physiological as well as pharmacologically stimulated apoptosis, ceramide can be considered a tumor-suppressor lipid. In contrast, sphingosine-1-phosphate can be considered a tumor-promoting lipid, and the enzyme responsible for its synthesis functions as an oncogene. Not surprisingly, genetic mutations that result in reduced ceramide generation, increased sphingosine-1-phosphate synthesis or which reduce steady state ceramide levels and increase sphingosine-1-phosphate levels have been identified as mechanisms of tumor progression and drug resistance in cancer cells. Pharmacological tools for modulating sphingolipid pathways are being developed and represent novel therapeutic strategies for the treatment of cancer.