Diverse functions of ceramide in cancer cell death and proliferation.

Ceramide, a bioactive sphingolipid, is now at the forefront of cancer research. Classically, ceramide is thought to induce death, growth inhibition, and senescence in cancer cells. However, it is now clear that this simple picture of ceramide no longer holds true. Recent studies suggest that there are diverse functions of endogenously generated ceramides, which seem to be context dependent, regulated by subcellular/membrane localization and presence/absence of direct targets of these lipid molecules. For example, different fatty-acid chain lengths of ceramide, such as C(16)-ceramide that can be generated by ceramide synthase 6 (CerS6), have been implicated in cancer cell proliferation, whereas CerS1-generated C(18)-ceramide mediates cell death. The dichotomy of ceramides' function in cancer cells makes some of the metabolic enzymes of ceramide synthesis potential drug targets (such as Cers6) to prevent cancer growth in breast and head and neck cancers. Conversely, activation of CerS1 could be a new therapeutic option for the development of novel strategies against lung and head and neck cancers. This chapter focuses on recent discoveries about the mechanistic details of mainly de novo-generated ceramides and their signaling functions in cancer pathogenesis, and about how these mechanistic information can be translated into clinically relevant therapeutic options for the treatment of cancer.