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7. Identifying a Novel Role of Glucosylceramide Synthase to Enhance Ceramide-Induced Cell Death in Head and Neck Squamous Cell Carcinoma

Presenters Name: 
Timothy Boyer
Co Presenters Name: 
Primary Research Mentor: 
Mark Kester
Secondary Research Mentor: 
Jeremy Shaw
Session: 
1
Abstract: 

Head and Neck Squamous Cell Carcinoma (HNSCC) is a cancer arising from the squamous cells of the oral and nasal cavities as well as the larynx and pharynx. Despite over 800,000 individuals being afflicted with this disease across the globe each year, current treatment options remain poor. Radiation and chemotherapy have a myriad of negative side effects, surgical operations in these areas often leave patients disfigured, and the three targeted therapies exhibit minimal therapeutic benefits. The Ceramide Nanoliposome (CNL) is a ~90nm liposome that incorporates the anti-proliferative, cell death-inducing sphingolipid, ceramide and is currently in FDA Phase-1 clinical trials. We have previously shown that CNL has promise in vitro for inducing greater cell death in HNSCC cell lines than non-cancerous Primary Gingival Fibroblasts (PGF). However, the role of ceramide metabolism on cell death has not been fully elucidated. Here, we identify a striking cell death-inducing role of glucosylceramide synthase (GCS), an enzyme previously reported to be pro-survival. Specifically, we show that GCS inhibitors, PPMP and Ibiglustat, have minimal effect as single agents, yet dramatically prevent CNL-induced death in multiple HNSCC cell lines. We further demonstrate that this effect on cell viability is concentration- and time-dependent via MTS and flow cytometry assays. Taken together, this work highlights the novel role of GCS to enhance ceramide-induced cell death and identifies a novel pathway to further sensitize HNSCC to CNL or to other targeted therapies.