Metabolizing Enzymes Such As Sphingomyelin Synthase Induce Cell Death by Increasing Ceramide Content

Summary

Ceramide, among its other roles, serves as a pro-apoptotic lipid mediator. Ceramide-induced pro-apoptotic signals include caspases, reactive oxygen species (ROS) and c-jun-N-terminal kinase (JNK), and anti-apoptotic signals such as phosphatidylinositides (PI)-3 kinase and protein kinase C are inhibited by ceramide. Sphingosine-1-phosphate (S1P) competes with ceramide-induced cell death by blocking its generation and downstream pathways. This balanced interaction between S1P and ceramide may regulate cell death and survival/growth. Regulating ceramide-metabolizing enzymes, such as sphingomyelin synthase (SMS) and glucosylceramide synthase (GCS), as well as those of ceramide-downstream pathways are crucial to control ceramide signals. It was recently shown that inhibiting SMS and GCS induced apoptotic cell death in human leukemia cell lines. In addition cells possessing less ceramide and have high levels of GCS and SMS were chemoresistant in vivo. Membranous SM generated by SMS1 gene, which we cloned, may act as not only the source for generation of ceramide but also as the platform for transmembrane receptors such as Fas antigen. Thus, overwhelming drug-or chemo-resistance in human hematopoietic malignancies by inhibiting ceramide-metabolizing enzymes and enhancing ceramide-downstream signals to intensify ceramide-induced cell death would be one approach to treating these cancers.