Additional Funding Sources
The project described was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant No. P20GM103408 and the Pardee Foundation.
Abstract
Sarcomas are rare, malignant tumors arising from connective tissues. Each year, approximately 12,000 people in the U.S. are diagnosed with sarcomas. Among them, osteosarcoma (bone) and synovial sarcoma (muscle) are aggressive pediatric sarcomas. Sphingomyelin is a cell membrane sphingolipid, which plays a key role in cell growth and mitosis. Sphingomyelin is upregulated in osteosarcoma and synovial sarcoma. The metabolic intermediate of the sphingolipid pathway, ceramide, is critical in cellular signal transduction and apoptotic pathways. The natural marine product jaspine B has been shown to inhibit sphingomyelin synthase, the enzyme that synthesizes sphingomyelin from ceramide. Jaspine B induced apoptosis in cancer cells by inhibiting sphingomyelin synthase, which resulted in an increase in ceramide. Jaspine B was effective at preventing tumor growth in intro and vivo. Cells treated with Jaspine B, responded by diverting excess ceramide into other branches of the sphingomyelin pathway. We observed a dynamic response to Jaspine B treatment in the sphingomyelin pathway that varied in vivo and in vitro.
Ceramide Inhibition Leads to Changes in the Sphingomyelin Pathway in Cancer
Sarcomas are rare, malignant tumors arising from connective tissues. Each year, approximately 12,000 people in the U.S. are diagnosed with sarcomas. Among them, osteosarcoma (bone) and synovial sarcoma (muscle) are aggressive pediatric sarcomas. Sphingomyelin is a cell membrane sphingolipid, which plays a key role in cell growth and mitosis. Sphingomyelin is upregulated in osteosarcoma and synovial sarcoma. The metabolic intermediate of the sphingolipid pathway, ceramide, is critical in cellular signal transduction and apoptotic pathways. The natural marine product jaspine B has been shown to inhibit sphingomyelin synthase, the enzyme that synthesizes sphingomyelin from ceramide. Jaspine B induced apoptosis in cancer cells by inhibiting sphingomyelin synthase, which resulted in an increase in ceramide. Jaspine B was effective at preventing tumor growth in intro and vivo. Cells treated with Jaspine B, responded by diverting excess ceramide into other branches of the sphingomyelin pathway. We observed a dynamic response to Jaspine B treatment in the sphingomyelin pathway that varied in vivo and in vitro.