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• W2034312306 abstract "Lymphangioleiomyomatosis (LAM) is a female predominant progressive and neoplastic disorder that leads to lung destruction and respiratory failure primarily in women. LAM is typically due to TSC2 mutations resulting in mTORC1 activation in proliferative smooth muscle-like cells in the lung. The female predominance of LAM suggests that estradiol contributes to disease development. Metabolomic profiling identified estradiol-enhanced prostaglandin biosynthesis signature in Tsc2-deficient cells, both in vitro and in vivo. Estradiol increased the expression of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis, which was increased at baseline in TSC2-deficient cells, and was not affected by rapamycin treatment, but decreased by Torin 1 treatment and Rictor knockdown, associated with reduction of levels phospho-Akt (S473). Prostaglandin production was also increased in TSC2-deficient cells. In preclinical models, Celecoxib or aspirin treatment suppressed tumor progression. LAM patients had significantly higherserum prostaglandin levels than healthy women. 15-epi-lipoxin-A4 was identified in exhaled breath condensate from LAM subjects and was increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. Targeting COX-2 and prostaglandin pathways may have therapeutic value in LAM and TSC-related diseases, and possibly in other conditions associated with mTOR-hyperactivation.Citation Format: Chenggang Li, Po-Shun Lee, Xiaoxiao Gu, Yang Sun, Erik Zhang, Alfredo Csibi, Jing Li, Carmen Priolo, Yanan Guo, Chin-Lee Wu, John Blenis, Kai-Feng Xu, Elizabeth Petri Henske, Bruce Levy, David Kwiatkowski, Jane J. Yu. Estradiol and mTORC2 orchestrate to enhance prostaglandin biosynthesis andtumorigenesis in tuberous sclerosis complex. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C59." @default.
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• W2034312306 date "2013-10-01" @default.
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• W2034312306 title "Abstract C59: Estradiol and mTORC2 orchestrate to enhance prostaglandin biosynthesis andtumorigenesis in tuberous sclerosis complex" @default.
• W2034312306 doi "https://doi.org/10.1158/1538-7445.fbcr13-c59" @default.
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