Mechanisms of Ceramide-Dependent Cancer Cell Death.

Mechanistic details for the roles of sphingolipids and their downstream targets in the regulation of tumor growth, response to chemo/radiotherapy, and metastasis have been investigated in recent studies using innovative molecular, genetic and pharmacologic tools in various cancer models. Induction of ceramide generation in response to cellular stress by chemotherapy, radiation, or exogenous ceramide analog drugs mediates cell death via apoptosis, necroptosis, or mitophagy. In this chapter, distinct functions and mechanisms of action of endogenous ceramides with different fatty acyl chain lengths in the regulation of cancer cell death versus survival will be discussed. In addition, importance of ceramide subcellular localization, trafficking, and lipid-protein binding between ceramide and various target proteins in cancer cells will be reviewed. Moreover, clinical trials from structure-function-based studies to restore antiproliferative ceramide signaling by activating ceramide synthesis will also be analyzed. Future studies are important to understand the mechanistic involvement of ceramide-mediated cell death in anticancer therapy, including immunotherapy.