Tuberin Regulates Prostaglandin Receptor–Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells
| العنوان: | Tuberin Regulates Prostaglandin Receptor–Mediated Viability, via Rheb, in mTORC1-Hyperactive Cells |
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| المؤلفون: | Xiaolei Liu, Elizabeth J. Kopras, Yang Liu, Chenggang Li, Anya Alayev, David R. Plas, Erik Zhang, Kantha Medepalli, Kouhei Masuda, Brian J. Siroky, David J. Kwiatkowski, Yang Sun, Marina K. Holz, Julia Sun, David Neal Franz, Michael T. Borchers, Darcy A. Krueger, Jamie K. Capal, Kathryn A. Wikenheiser-Brokamp, Jane J. Yu, Andrew R. Osterburg, Na Li, Maxwell Mays |
| المصدر: | Molecular Cancer Research. 15:1318-1330 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, Lung Neoplasms, Cell Survival, Angiomyolipoma, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, Mice, 03 medical and health sciences, Tuberous sclerosis, Downregulation and upregulation, Cell Line, Tumor, Tuberous Sclerosis Complex 2 Protein, medicine, Animals, Humans, Lymphangioleiomyomatosis, Child, Prostaglandin receptor, Receptor, Molecular Biology, Sulfonamides, Epilepsy, Tumor Suppressor Proteins, Brain, Infant, medicine.disease, Kidney Neoplasms, Up-Regulation, nervous system diseases, 030104 developmental biology, medicine.anatomical_structure, Oncology, Child, Preschool, Mutation, Receptors, Prostaglandin E, EP3 Subtype, biology.protein, Cancer research, Female, Ras Homolog Enriched in Brain Protein, lipids (amino acids, peptides, and proteins), TSC1, TSC2, RHEB |
| الوصف: | Tuberous sclerosis complex (TSC) is a tumor-suppressor syndrome affecting multiple organs, including the brain, skin, kidneys, heart, and lungs. TSC is associated with mutations in TSC1 or TSC2, resulting in hyperactivation of mTOR complex 1 (mTORC1). Clinical trials demonstrate that mTORC1 inhibitors decrease tumor volume and stabilize lung function in TSC patients; however, mTOR inhibitors are cytostatic not cytocidal, and long-term benefits and toxicities are uncertain. Previously, we identified rapamycin-insensitive upregulation of cyclooxygenase 2 (PTGS2/COX2) and prostaglandin E2 (PGE2) production in TSC2-deficient cells and postulated that the action of excess PGE2 and its cognate receptors (EP) contributes to cell survival. In this study, we identify upregulation of EP3 (PTGER3) expression in TSC2-deficient cells, TSC renal angiomyolipomas, lymphangioleiomyomatosis lung nodules, and epileptic brain tubers. TSC2 negatively regulated EP3 expression via Rheb in a rapamycin-insensitive manner. The EP3 antagonist, L-798106, selectively suppressed the viability of TSC2-deficient cells in vitro and decreased the lung colonization of TSC2-deficient cells. Collectively, these data reveal a novel function of TSC2 and Rheb in the regulation of EP3 expression and cell viability. Implications: Therapeutic targeting of an aberrant PGE2-EP3 signaling axis may have therapeutic benefit for TSC patients and for other mTOR-hyperactive neoplasms. Mol Cancer Res; 15(10); 1318–30. ©2017 AACR. |
| تدمد: | 1557-3125 1541-7786 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::59c46b81a990633960c5b18a7060006bTest https://doi.org/10.1158/1541-7786.mcr-17-0077Test |
| رقم الانضمام: | edsair.doi.dedup.....59c46b81a990633960c5b18a7060006b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573125 15417786 |
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