Ceramide-orchestrated signalling in cancer cells

Key Points Ceramide is a sphingolipid consisting of sphingosine, an 18-carbon unsaturated amino alcohol hydrocarbon chain, which is joined by an amide linkage to a fatty acid of varying chain length and a varying degree of saturation. The type of fatty acyl group that is attached often dictates the biological activities of ceramide. Through its capacity to induce programmed cell death (apoptosis), ceramide can function as a potent tumour suppressor lipid. Ceramide can also limit cancer cell proliferation by blocking cell cycle transition. Ceramide can also instigate autophagic responses in cancer cells; however, these may yield survival or lethal outcomes. Cancer cells exert tight control over the metabolism of ceramide. As a survival mode, cancer cells upregulate enzymes that metabolize ceramide, which results in muted apoptotic responses and/or the promotion of mitogenicity, depending on the routes by which ceramide is metabolized. Ceramide signalling in cancer cells enlists extrinsic signalling, which originates outside the cell, or intrinsic signalling (also known as the mitochondrial pathway) that originates from within the cell, to signal to downstream beacons of cellular response. These responses can be caspase (protease)-dependent or caspase-independent. Key players in ceramide signalling in cancer are protein phosphatase 2A, p38, JUN N-terminal kinase (JNK), AKT, protein kinase Cζ (PKCζ) and survivin, proteins that communicate and reinforce tumour cell demise and/or the arrest of the cell cycle at G1 and G2 phases. Because of its ability to induce apoptosis, ceramide holds promise as an anticancer agent. Ceramide-based therapies are being developed through the use of ceramide-generating agents, such as fenretinide, and by the use of exogenous cell-permeable short-chain ceramides, such as C6 ceramide. With both avenues, the effect of ceramide can be magnified by the inclusion of agents that block cancer cell-mediated elimination of ceramide. Ceramide induces apoptosis, autophagy and cell cycle arrest and it is therefore often metabolized in tumour cells to suppress its function and promote proliferation. As also discussed in this Review, there are efforts to increase ceramide levels as a therapeutic avenue. One crucial barrier to progress in the treatment of cancer has been the inability to control the balance between cell proliferation and apoptosis: enter ceramide. Discoveries over the past 15 years have elevated this sphingolipid to the lofty po