Roles of bioactive sphingolipids in cancer biology and therapeutics

Abstract

In this chapter, roles of bioactive sphingolipids in the regulation of cancer pathogenesis and therapy will be reviewed. Sphingolipids have emerged as bioeffector molecules, which control various aspects of cell growth, proliferation, and anti-cancer therapeutics. Ceramide, the central molecule of sphingolipid metabolism, generally mediates anti-proliferative responses such as inhibition of cell growth, induction of apoptosis, and/or modulation of senescence. On the other hand, sphingosine 1-phosphate (S1P) plays opposing roles, and induces transformation, cancer cell growth, or angiogenesis. A network of metabolic enzymes regulates the generation of ceramide and S1P, and these enzymes serve as transducers of sphingolipid-mediated responses that are coupled to various exogenous or endogenous cellular signals. Consistent with their key roles in the regulation of cancer growth and therapy, attenuation of ceramide generation and/or increased S1P levels are implicated in the development of resistance to drug-induced apoptosis, and escape from cell death. These data strongly suggest that advances in the molecular and biochemical understanding of sphingolipid metabolism and function will lead to the development of novel therapeutic strategies against human cancers, which may also help overcome drug resistance.

Fig. 16.1

Sphingolipid metabolism. Sphingolipids are comprised of three main components: a sphingosine backbone, a fatty-acid chain, and a head group. Characteristics of sphingolipids change based on the head group, and recently, it was shown that the fatty-acid chain length could influence sphingolipid function. Ceramide is central in sphingolipid metabolism. Ceramide can be generated through several pathways, in particular it can be synthesized de novo from palmitoyl CoA and serine. Also, interestingly, ceramide, which is a pro-apoptotic sphingolipid, can proceed on to form S1P, a pro-survival sphingolipid. Thus, sphingolipid metabolic enzymes play a crucial role in determining the fate of cancer cells

Fig. 16.2. De novo

generation of ceramide via the function of dhCerS. Recently identified dhCerS1–6 are responsible for the generation and determining the fatty-acid chain length of ceramide in the de novo pathway. For example, dhCerS1, previously known as LASS1, is responsible for generating dihydro-C₁₈-ceramide, whereas CersS2 and CerS4 synthesize dihydro-C₂₂-, C₂₄-, and C₂₆-ceramides. In addition, dihydro-C₁₂-, C₁₄- and C₁₆-ceramides are generated by CerS5 and CerS6. These dihydro-ceramides are then desaturated to form ceramides by DES

Fig. 16.3

Ceramide and S1P signaling in cancer cells. Ceramide signaling mainly occurs through the regulation of its immediate and direct targets, leading to apoptosis, growth arrest, and senescence. Conversely, when ceramide is metabolized into S1P, cells will undergo cellular transformation, anti-apoptosis, or induction of angiogenesis. Conversion of ceramide to SM leads to the liberation of DAG from PC, and DAG is a known activator of PKC, which is involved in promoting cellular proliferation. Also, ceramide can be further metabolized into glucosylceramide, which leads to drug resistance. Phosphorylation of ceramide by CK to generate C1P also associated with induction of cell growth. Thus, these data support the hypothesis that while ceramide induces anti-proliferation, alterations in its generation and/or accumulation might result in pro-survival and anti-apoptosis

Fig. 16.4

Roles of ceramide and S1P in anti-cancer therapeutics. The cellular balance between ceramide in tumor samples and S1P is believed to determine the fate of cancer cells. Often, within a tumor, there are altered levels/accumulation of ceramide (such as low C₁₈-ceramide levels in HNSCC) and high S1P levels, which are often secreted into the serum at relatively high concentrations. This causes the metabolic balance to favor S1P resulting in a pro-survival outcome. However, new therapies are being explored to shift this balance in favor of ceramide. Ultimately, these new treatments are aimed at increasing ceramide levels while inhibiting S1P generation, secretion, or signaling through S1PRs