Tuberin Regulates Prostaglandin Receptor-mediated Viability, via Rheb, in mTORC1-hyperactive Cells

摘要: Tuberous sclerosis complex (TSC) is a tumor-suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC associated with mutations in TSC1 or TSC2, resulting hyperactivation of mTOR 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume stabilize lung function patients; however, are cytostatic not cytocidal, long-term benefits toxicities uncertain. Previously, we identified rapamycin-insensitive upregulation cyclooxygenase 2 (PTGS2/COX2) prostaglandin E2 (PGE2) production TSC2-deficient cells postulated action excess PGE2 its cognate receptors (EP) contributes to cell survival. In this study, identify EP3 (PTGER3) expression cells, renal angiomyolipomas, lymphangioleiomyomatosis nodules, epileptic brain tubers. TSC2 negatively regulated via Rheb manner. The antagonist, L-798106, selectively suppressed viability vitro decreased colonization cells. Collectively, these data reveal novel regulation viability.Implications: Therapeutic targeting an aberrant PGE2-EP3 signaling axis may have therapeutic benefit for patients other mTOR-hyperactive neoplasms. Mol Cancer Res; 15(10); 1318-30. ©2017 AACR.