Regulation of lactosylceramide synthase (glucosylceramide beta1-->4 galactosyltransferase); implication as a drug target.

Lactosylceramide is a ubiquitously present glycosphingolipid in mammalian tissues and has been implicated in cell proliferation, adhesion, migration and angiogenesis. This glycosphingolipid is synthesized by Golgi-localized enzyme LacCer synthase. According to recent nomenclature and gene mapping studies, two LacCer synthases beta1,4GalT-V and beta1,4GalT-VI have been identified and characterized. In addition, beta1,4GalT-V has been implicated in the synthesis of N-glycans of cell surface glycoproteins. During the past two decades data have accumulated suggesting that the cellular level of LacCer can be regulated by various growth factors, cytokines, lipids, lipoproteins and hemodynamic factors, such as fluid shear stress, by altering the activity of LacCer synthase. An interesting feature is that a nuclear regulating factor (SP1) plays a critical role in transcriptional regulation of this enzyme in cancer cells. Moreover, in human umbilical vein endothelial cells, NF-kappaB has been also shown to regulate this enzyme which, in turn, regulates the gene/protein expression of platelet endothelial cell adhesion molecule, intercellular cell adhesion molecule and angiogenesis. Since new blood supply via formation of capillaries is critical in tumor growth, metastasis, and atherogenesis, these findings expand the role of enzyme in these pathologies. Additional studies are warranted to understand the molecular and biochemical basis of how LacCer synthases are regulated. These studies will facilitate advances in discovery of drugs which mitigate diseases, such as atherosclerosis and cancer due to an aberrant regulation of these LacCer synthases.