title: Glucosylceramidases and malignancies in mammals.
abstract: Sphingolipids represent a major class of lipids that are essential constituents of eukaryotic cells. They are predominantly located in plasma membrane microdomains, and play an important structural role in regulating membrane fluidity. They are also bioactive effectors involved in diverse key cellular functions such as apoptosis and proliferation. The implication of some sphingolipids in cancer is well established whereas that of some others is still a matter of intense investigation. Glucosylceramide is the backbone of more than 300 structurally different glycosphingolipids including gangliosides and sulfatides, and is essential for mammalian development. Therefore, glucosylceramidases (also named GBA1, GBA2 and GBA3 β-glucosidases), the enzymes that hydrolyse β-glucosylceramide, play important functions. GBA1 is a lysosomal hydrolase whose deficiency causes Gaucher disease, the most prevalent inherited lysosomal storage disorder. GBA2 is a ubiquitous non-lysosomal glucosylceramidase whose mutations have been associated with some forms of hereditary spastic paraplegia. GBA3 is a cytosolic β-glucosidase, mostly present in the kidney, liver, spleen, intestine and lymphocytes of mammals, the function of which is still unclear. Whereas glucosylceramide synthase is implicated in multidrug resistance, the role of glucosylceramide breakdown in cancer is not yet fully appreciated. Defective GBA1 enzyme activity in humans, i.e., Gaucher disease, is associated with an increased risk of multiple myeloma and other malignancies. Putative molecular links between Gaucher disease and cancer, which might implicate the malignant cell and/or its microenvironment, are reviewed. The functions of GBA2 and GBA3 in cancer progression are also discussed.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Toulouse, France; Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Toulouse, France; Service de Médecine Interne, CHU Purpan, Toulouse, France. Electronic address: leonardo.astudillo31@gmail.com.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Astudillo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Toulouse, France; Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Toulouse, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Therville
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Toulouse, France; Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Colacios
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Toulouse, France; Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Toulouse, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ségui
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Toulouse, France; Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Andrieu-Abadie
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) UMR1037, Toulouse, France; Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Toulouse, France; Laboratoire de Biochimie Métabolique, Institut Fédératif de Biologie, CHU Purpan, Toulouse, France. Electronic address: thierry.levade@inserm.fr.
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
mesh_terms: D000818:Animals; D002518:Ceramides / Q000235:genetics / Q000378:metabolism; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics; D006801:Humans; D010694:Lactase-Phlorizin Hydrolase / Q000235:genetics* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology
chemical_list: D002518:Ceramides; D009363:Neoplasm Proteins; D010694:Lactase-Phlorizin Hydrolase
keywords: Ceramide; Gaucher disease; Glucosylceramidase; Glucosylceramide; Melanoma