title: Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells.
abstract: Lymphangioleiomyomatosis (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.
authors.affiliation: Pulmonary and Critical Care Medicine, 2 Translational Medicine, Department of Medicine, Brigham and Women's Hospital-Harvard Medical School, Boston, MA 02115.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Li
authors.forename: Po-Shun
authors.initials: PS
authors.lastname: Lee
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Gu
authors.forename: Erik
authors.initials: E
authors.lastname: Zhang
authors.forename: Yanan
authors.initials: Y
authors.lastname: Guo
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Wu
authors.forename: Neil
authors.initials: N
authors.lastname: Auricchio
authors.forename: Carmen
authors.initials: C
authors.lastname: Priolo
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Alfredo
authors.initials: A
authors.lastname: Csibi
authors.forename: Andrey
authors.initials: A
authors.lastname: Parkhitko
authors.forename: Tasha
authors.initials: T
authors.lastname: Morrison
authors.forename: Anna
authors.initials: A
authors.lastname: Planaguma
authors.forename: Shamsah
authors.initials: S
authors.lastname: Kazani
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Xu
authors.forename: Elizabeth Petri
authors.initials: EP
authors.lastname: Henske
authors.forename: John
authors.initials: J
authors.lastname: Blenis
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
authors.forename: David
authors.initials: D
authors.lastname: Kwiatkowski
authors.forename: Jane J
authors.initials: JJ
authors.lastname: Yu
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001944:Breath Tests; D063646:Carcinogenesis / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D044045:Lipoxins / Q000032:analysis; D018192:Lymphangioleiomyomatosis / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D055432:Metabolomics; D051379:Mice; D016513:Mice, SCID; D018613:Microscopy, Confocal; D046912:Multiprotein Complexes / Q000378:metabolism*; D009287:Naphthyridines / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis* / Q000097:blood; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D060888:Real-Time Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000172:deficiency
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; D002352:Carrier Proteins; D044045:Lipoxins; D046912:Multiprotein Complexes; D009287:Naphthyridines; D011453:Prostaglandins; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C040527:lipoxin A4; D004958:Estradiol; D051546:Cyclooxygenase 2; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D001241:Aspirin