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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 or 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 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. Therapeutic targeting of an aberrant PGE2-EP3 signaling axis may have therapeutic benefit for TSC patients and for other mTOR-hyperactive neoplasms. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0077 | DOI Listing |
Lymphangioleiomyomatosis (LAM) is a cystic lung disease that primarily affects women. LAM is caused by the invasion of metastatic smooth muscle-like cells into the lung parenchyma, leading to abnormal cell proliferation, lung remodeling and progressive respiratory failure. LAM cells have TSC gene mutations, which occur sporadically or in people with Tuberous Sclerosis Complex.
View Article and Find Full Text PDFAm J Respir Cell Mol Biol
November 2024
Research Institute of the McGill University Health Centre, Respiratory Program and Meakins-Christie Laboratories, Montreal, Quebec, Canada.
Life Sci Alliance
November 2024
Department of Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark
The mTORC1-complex is negatively regulated by TSC1 and TSC2. Activation of Hedgehog signaling is strictly dependent on communication between Smoothened and the Hedgehog-signaling effector and transcription factor, GLI2, in the primary cilium. Details about this communication are not known, and we wanted to explore this further.
View Article and Find Full Text PDFBackground: Aberrant activation of mTORC1 is clearly defined in TSC, causing uncontrolled cell growth. While mTORC1 inhibitors show efficacy to stabilise tumour growth in TSC, they are not fully curative. Disease facets of TSC that are not restored with mTOR inhibitors might involve NF-κB.
View Article and Find Full Text PDFOrphanet J Rare Dis
June 2024
Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China.
Objective: This study aimed to enhance the understanding of the role of estrogen in lymphangioleiomyomatosis(LAM) and to conclude the impact of estrogen-altering events on the condition and recent advances in estrogen-based treatments for LAM.
Results: LAM development is strongly linked to mutations in the tuberous sclerosis gene (TSC1/2) and the presence of estrogen. Estrogen plays a significant role in the spread of TSC2-deficient uterine leiomyoma cells to the lungs and the production of pulmonary LAM.
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