Dysregulation of Sphingolipid Metabolism and Actions in Tuberous Sclerosis Complex
[Technical Report, Annual Report]
CINCINNATI UNIV OH
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TSC is an autosomal dominant disorder with multi-system manifestations including tumors in the brain, heart, kidneys, and lung. TSC is caused by germline inactivating mutations in the tuberin genes, TSC1 or TSC2, that inhibit the activation of mTORC1. Recent advancements have demonstrated that treatment with mTORC1 inhibitors rapamycin or everolimus are effective in arresting the growth of symptomatic tumors. The tumors regrow and symptoms resume when treatment is discontinued, suggesting a cytostatic rather than a cytocidal effect, and therefore, the need for continuous therapy with all the concerns associated with chronic treatment to consider. A major breakthrough is needed to advance therapy for TSC. A long-term strategy our laboratory has been to discover novel molecular mechanisms responsible for the survival advantage of TSC tumor cells. For this proposal, we found that dihydroceramide desaturase DEGS1 and acid ceramidase ASAH1, enzymes critical to regulating the cellular concentration of the cell survival sphingosine-1-phosphate S1P, and S1P receptor S1PR1 that mediates S1P function, were all aberrantly upregulated in TSC tumor cells, but not in normal cells. Our own preliminary data not only confirms this differential expression but also silencing of ASAH1 and S1PR1 in vitro promotes the death of TSC cells. These results suggest that sphingolipid metabolism maybe a previously unappreciated driver of cell survival in TSC and are potential biomarkers for disease severity and therapeutic response in TSC.
- Medicine and Medical Research