Gaucher's disease and cancer: a sphingolipid perspective

Abstract

Gaucher's disease is a sphingolipidosis characterized by a specific deficiency in an acidic glucocerebrosidase, which results in aberrant accumulation of glucosylceramide primarily within the lysosome. Gaucher's disease has been correlated with cases of myeloma, leukemia, glioblastoma, lung cancer, and hepatocellular carcinoma, although the reasons for the correlation are currently being debated. Some suggest that the effects of Gaucher's disease may be linked to cancer, while others implicate the therapies used to treat Gaucher's disease. This debate is not entirely surprising, as the speculations linking Gaucher's disease with cancer fail to address the roles of ceramide and glucosylceramide in cancer biology. In this review, we will discuss, in the context of cancer biology, ceramide metabolism to glucosylceramide, the roles of glucosylceramide in multidrug-resistance, and the role of ceramide as an anticancer lipid. This review should reveal that it is most practical to associate elevated glucosylceramide, which accompanies Gaucher's disease, with the progression of cancer. Furthermore, this review proposes that the therapies used to treat Gaucher's disease, which augment ceramide accumulation, are likely not linked to correlations with cancer.

FIGURE 1. Ceramide metabolism

Ceramide serves as the hypothetical center of sphingolipid metabolism. Ceramide is generated de novo from the condensation of palmitoyl-CoA with serine, in a process producing intermediate metabolites, 3-ketosphinganine, sphinganine (dihydrosphingosine), and dihydroceramide. Ceramide can be phosphorylated to ceramide-1-phosphate, can be broken down to sphingosine and then phosphorylated to sphingosine-1-phosphate, or can be converted to sphingomyelin or glycosphingolipids via head group addition. Glucosylceramide synthase (GCS) catalyzes the conversion of ceramide to glucosylceramide while acidic glucocerebrosidase (GBA), the enzyme defective in Gaucher’s disease, removes glucose to regenerate ceramide. SPT: serine palmitoyltransferase; CS: ceramide synthase; DES: dihydroceramide desaturase; GALC: galactosylceramidase (galacto-cerebrosidase); GALT: ceramide galactosyltransferase; GCS: glucosylceramide synthase; SMase: sphingomyelinase; SMS: sphingomyelin synthase; PC: phosphatidylcholine; DAG: diacylglycerol; CDase: ceramidase; C1PP: ceramide-1-phosphate phosphatase; CK: ceramide kinase; S1PP: sphingosine-1-phosphate phosphatase; SK: sphingosine kinase.

FIGURE 2. Protein junctures for the action of glucosylceramide synthase inhibitors and P-glycoprotein antagonists

P-glycoprotein (P-gp) directed transport of glucosylceramide into the Golgi. Upon conversion of ceramide to glucosylceramide by glucosylceramide synthase (GCS), glucosylceramide is transported into the Golgi lumen by P-gp for conversion to higher glycosphingolipids. Inhibitors of ceramide glycosylation exert effects at either GCS, P-gp, or both. LCS: lactosylceramide synthase.

FIGURE 3. Glucosylceramide blocks the assembly of the NADPH oxidase

The NADPH oxidase is composed of two membrane-bound subunits (rectangles: gp91^phox, p22^phox) and three cytosilic subunits (circles: p40^phox, p47^phox, p67^phox). In response to stimulation by chemotherapeutics, or inflammatory mediators, ceramide stimulates assembly and activation of the NADPH oxidase. An active NADPH oxidase can mediate redox-sensitive signaling as well as cell death pathways. In contrast, glucosylceramide blocks assembly of the cytosolic subunits with the membrane subunits by promoting changes in membrane curvature. Therefore, glucosylceramide blocks NADPH oxidase-mediated redox-signaling and cell death pathways.