Li, ChenggangLee, Po-ShunSun, YangGu, XiaoxiaoZhang, ErikGuo, YananWu, Chin-LeeAuricchio, NeilPriolo, CarmenLi, JingCsibi, AlfredoParkhitko, AndreyMorrison, TashaPlanaguma, AnnaKazani, SIsrael, ElliotXu, Kai-FengHenske, ElizabethBlenis, JohnLevy, BruceKwiatkowski, DavidYu, Jane J2014-08-132014Li, C., P. Lee, Y. Sun, X. Gu, E. Zhang, Y. Guo, C. Wu, et al. 2014. “Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells.” The Journal of Experimental Medicine 211 (1): 15-28. doi:10.1084/jem.20131080. http://dx.doi.org/10.1084/jem.20131080.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:12717476Lymphangioleiomyomatosis (LAM) is a progressive neoplastic disorder that leads to lung destruction and respiratory failure primarily in women. LAM is typically caused by tuberous sclerosis complex 2 (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 an estradiol-enhanced prostaglandin biosynthesis signature in Tsc2-deficient (TSC−) 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 also increased at baseline in TSC-deficient cells and was not affected by rapamycin treatment. However, both Torin 1 treatment and Rictor knockdown led to reduced COX-2 expression and phospho-Akt-S473. Prostaglandin production was also increased in TSC-deficient cells. In preclinical models, both Celecoxib and aspirin reduced tumor development. LAM patients had significantly higher serum 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. In vitro, 15-epi-lipoxin-A4 reduced the proliferation of LAM patient–derived cells in a dose-dependent manner. 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.en-USJournal Article2014-08-1310.1084/jem.20131080