Prostaglandin biosynthesis: a novel therapeutic target in TSC disorders

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DESCRIPTION (provided by applicant): Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with multi-system manifestations including seizures, mental retardation, autism, and tumors in the brain, heart, skin, kidney, and lung. 80% of TSC patients develop renal angiomyolipomas; cysts and carcinomas also occur. TSC is caused by germline inactivating mutations in TSC1 or TSC2, which encode hamartin (TSC1) and tuberin (TSC2), respectively. TSC1 and TSC2 function as a complex to inhibit mammalian target of rapamycin (mTOR) complex 1 (mTORC1), and tumors from TSC patients show hyperactivation of mTORC1. mTORC1 is a key regulator of protein synthesis, cell growth and cellular metabolism. Treatment with rapamycin or everolimus, mTORC1 inhibitors, partially decreases the volume of renal angiomyolipomas and brain tumors in TSC, but tumors regrow when treatment is discontinued. The long-term benefits and hazards of rapamycin are uncertain. Our central hypothesis is that loss of TSC2 enhances the expression and activity of components in phospholipase A2-cyclooxygenases-prostaglanin receptors (PAL2-COX1/2-EP3) pathways, and thereby leads to enhanced production of prostaglandins and promotes TSC-related tumor development. The long-term goal of this proposal is to identify the molecular mechanisms and significance of TSC2-dependent and mTORC1-independent up-regulation of COX-2 and prostaglandin biosynthesis, and thereby facilitate the potential application of prostaglandins as biomarkers of disease severity, and the development of prostaglandin inhibitors as therapeutic approaches for tumors occurring in TSC, and tumors with TSC1/TSC2 involvement occurring in non-TSC patients.