A Novel Signaling Pathway that Governs Tumor Metastasis: Ceramide Regulates Direct Crosstalk Between TGF-ß and Sonic Hedgehog Signaling

In the past twenty years, specific sphingolipids have become recognized for their participation in membrane functions and signaling events that control a wide array of cellular processes. Ceramide is considered as a main molecule of bioactive sphingolipid metabolites, are involved in signaling pathways that regulate cell proliferation, apoptosis, motility, differentiation, and angiogenesis. More recent studies have introduced bioactive sphingolipids and their metabolic enzymes take a role as regulated component in migration and cell mobility processes. However, the molecular mechanism of ceramide involved is unknown. Here, we investigated the effect of ceramide synthases (CerS) and ceramide on migration and its related signal pathways in situ and in vivo model. Interestingly, our data show that among CerS only CerS4/ceramide is involved to cell migration and tumor metastasis. Here, we also have generated CerS4−/− mice for in vivo studies. Excitingly, we observed that genetically loss of CerS4 resulted in ...