β-Galactosylceramidase in cancer: more than a psychosine scavenger

Abstract

Sphingolipids, a class of compounds composed by a sphingoid base backbone, represent major components of biological membranes, and play a pivotal role in a variety of subcellular signaling processes. Abnormal sphingolipid metabolism sets the basis for the pathogenesis of variety of genetic diseases known collectively as sphingolipidosis, or sphingolipodystrophy. Among them, globoid cell leukodystrophy (also named Krabbe disease; OMIM #245200), is an autosomal recessive sphingolipidosis characterized by degeneration of oligodendroglia and progressive demyelination due to the genetic deficiency of β-galactosylceramidase (GALC; EC 3.2.1.46) [1], a lysosomal acid hydrolase that catalyzes the removal of β-galactose from β-galactosylceramide (GalCer) and other terminal β-galactose-containing sphingolipids. Based on a long-held and recently confirmed “psychosine hypothesis” [2], Krabbe disease may manifest as a consequence of the accumulation of the neurotoxic GALC substrate β-galactosylsphingosine (psychosine) in the central and peripheral nervous system [3]. Thus, most of the studies concerning the biological role of GALC have been performed on Krabbe patients and Galc-deficient twitcher mice (an authentic animal model of the disease [4]), leading to the envision that the major biological function of GALC may consist in its psychosine “scavenging” activity. However, experimental evidence indicates that GALC may act not only as a psychosine scavenger, but its modulation also exerting a series of psychosineindependent effects [5, 6]. For instance, GALC deficiency affects neovascularization in in vitro and in vivo in the presence of negligible, if any changes in psychosine levels [7, 8]. In addition, knock-down of the human GALC ortholog galcb in zebrafish embryos affects cell survival and neuronal differentiation in the absence of any significant accumulation of this metabolite [9]. In this frame, a recent study has shown that Galc knockdown in murine melanoma B16 cells causes a significant increase of the levels of the oncosuppressive sphingolipid ceramide mirrored by a decrease of sphingomyelins, phosphatidylethanolamines and cholesteryl esters, paralleled by an increased concentration of diacylglycerols [10]. These alterations of the lipidomic profile resulted in the inhibition of the tumorigenic activity of murine melanoma B16 cells. Increased levels of ceramide were observed also in GALC-silenced human melanoma A2058 cells and tumor xenografts, with a consequent decrease of their tumorigenic potential [10]. In keeping with these observations, a progressive increase of GALC expression occurs during tumor progression in human pathological skin specimens ranging from common nevi to stage IV melanoma. Again, the levels of GALC expression were inversely related to the levels of ceramide immunoreactivity in the same tumor samples [5, 10]. Together, these findings indicate that GALC might act as an oncogenic enzyme during melanoma progression by decreasing the levels of the oncosuppressive ceramide. These data also bring up the question of the mechanisms responsible for the observed inverse relationship that occurs between GALC activity and ceramide levels in melanoma. In this frame, we have observed that GALC down-regulation in murine and human melanoma cells leads to a non-redundant upregulation of sphingomyelin phosphodiesterase 3 (Smpd3) [10]. This gene encodes for neutral sphingomyelinase 2, an oncosuppressive enzyme that catalyzes the hydrolysis of sphingomyelin to form phosphocholine and ceramide ([11] and references Editorial