Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses

Abstract

The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to β-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of β-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of β-glucosylceramide. The previously described mechanistic links between lysosomal β-glucosylceramidase, β-glucosylceramide and/or β-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the β-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.

Keywords: acid ceramidase; ceramide; glucocerebrosidase; glucosylsphingosine; melanoma; myeloma; sphingosine.

Figure 1

Glucosylceramide structure and metabolism. Abbreviations: Cer, ceramide; FA, fatty acid; Glc, glucose; GSL, glycosphingolipid; Sph, sphingosine; S1P, sphingosine 1-phosphate; SphK, sphingosine kinase. Fatty acids found in GlcCer usually include C16:0, C18:0, C22:0 and C24:1.

Figure 2

Melanoma tumor growth is increased in Gba1^D409V/null mice. (A,B) GCase enzyme activity was assessed in lysates of liver (A) and spleen (B) isolated from D409V/null mice (D409V/null) or homozygous wild-type littermates (wt/wt) having the same mixed genetic background. Assays were performed in duplicate on samples of three to six animals (18–22 weeks of age). (C,D) 3 × 10⁵ B16F10 melanoma cells were injected subcutaneously into wt/wt or D409V/null mice (19–22 weeks of age). Tumor volumes were measured every 3 days (C). Tumor and spleen weights were measured 25 days after tumor inoculation. Data are expressed as means ± SEM of at least two independent experiments (n = 7–21 mice). Statistical differences were determined using the Mann–Whitney test. Asterisks indicate statistically significant differences: *, p < 0.05; **, p < 0.01; ****, p < 0.0001.