Pharmacological Inhibition of Serine Palmitoyl Transferase and Sphingosine Kinase-1/-2 Inhibits Merkel Cell Carcinoma Cell Proliferation
Abstract
Merkel cell carcinoma (MCC), a highly aggressive neuroendocrine skin cancer, is primarily linked to infection by Merkel cell polyomavirus (MCPyV). The virus’s ability to bind, enter, and infect cells is facilitated by glycosphingolipids. In addition to their role as receptors, bioactive sphingolipids are increasingly recognized as key regulators of several cancer characteristics. Both MCPyV-positive and MCPyV-negative MCC cells express subunits of serine palmitoyl transferase (SPT) and mRNA for sphingosine kinases (SK) 1/2. When the expression of MCPyV large tumor antigen was induced in human lung fibroblasts, it led to an increase in SPTLC1-3 and SK1/2 levels. Based on this, we investigated the potential of pharmacologically inhibiting sphingolipid metabolism to disrupt the proliferation of MCPyV-positive MCC cell lines. We used myriocin (an antagonist of serine palmitoyl transferase) along with two SK inhibitors (SKI-II and ABC294640). In MKL-1 and WaGa cells, myriocin reduced the levels of ceramide, sphingomyelin, and sphingosine-1-phosphate, while SKI-II increased ceramide species but lowered sphingomyelin and sphingosine-1-phosphate concentrations. These alterations in sphingolipid balance were linked to decreased cell viability, increased necrosis, cleavage of procaspase-3 and PARP, activation of caspase-3, and reduced phosphorylation of AKT at serine 473. Both myriocin and SKI-II led to smaller tumor sizes and less Ki-67 staining in xenografted MKL-1 and WaGa tumors on the chorioallantoic membrane. These findings suggest that targeting sphingolipid metabolism could offer a promising therapeutic strategy for MCC.