• Chenggang Li, Po-Shun Lee, Yang Sun, Xiaoxiao Gu, Erik Zhang, Yanan Guo, Chin-Lee Wu, Neil Auricchio, Carmen Priolo, Jing Li, Alfredo Csibi, Andrey Parkhitko, Tasha Morrison, Anna Planaguma, Shamsah Kazani, Elliot Israel, Kai-Feng Xu, Elizabeth Petri Henske, John Blenis, Bruce D Levy, David Kwiatkowski, and Jane J Yu.
• Pulmonary and Critical Care Medicine, 2 Translational Medicine, Department of Medicine, Brigham and Women's Hospital-Harvard Medical School, Boston, MA 02115.
• J. Exp. Med. 2014 Jan 13; 211 (1): 15-28.

AbstractLymphangioleiomyomatosis (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.

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