Potential Role of Sphingolipidoses-Associated Lysosphingolipids in Cancer

SIMPLE SUMMARY: Sphingolipidoses are a subgroup of rare inherited disorders of lipid metabolism, most often due to a lysosomal enzymatic defect affecting sphingolipid catabolism. They are characterized by the accumulation of sphingolipids and their deacylated derivatives, called lysosphingolipids. An increased occurrence of cancer is suspected in some of these disorders. Whether lysosphingolipids are involved is unknown, and there is little data available on this topic. Here, we review the literature on lysosphingolipids and their potential effects on cellular properties, which could contribute to cancer development. Finally, we present data showing that one of them (namely, glucosylsphingosine) induces modifications of melanoma cells, which may favor tumor progression. Our review highlights that a better knowledge of lysosphingolipids, the biomarkers of rare diseases, could contribute to a better understanding of the pathophysiology of cancer. ABSTRACT: Sphingolipids play a key structural role in cellular membranes and/or act as signaling molecules. Inherited defects of their catabolism lead to lysosomal storage diseases called sphingolipidoses. Although progress has been made toward a better understanding of their pathophysiology, several issues still remain unsolved. In particular, whether lysosphingolipids, the deacylated form of sphingolipids, both of which accumulate in these diseases, are simple biomarkers or play an instrumental role is unclear. In the meanwhile, evidence has been provided for a high risk of developing malignancies in patients affected with Gaucher disease, the most common sphingolipidosis. This article aims at analyzing the potential involvement of lysosphingolipids in cancer. Knowledge about lysosphingolipids in the context of lysosomal storage diseases is summarized. Available data on the nature and prevalence of cancers in patients affected with sphingolipidoses are also reviewed. Then, studies investigating the biological effects of lysosphingolipids toward pro or antitumor pathways are discussed. Finally, original findings exploring the role of glucosylsphingosine in the development of melanoma are presented. While this lysosphingolipid may behave like a protumorigenic agent, further investigations in appropriate models are needed to elucidate the role of these peculiar lipids, not only in sphingolipidoses but also in malignant diseases in general.