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: 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, Jane J Yu
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 211 Issue 1 Pg. 15-28 (Jan 13 2014) ISSN: 1540-9538 [Electronic] United States
• PMID: 24395886 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• 1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one
• Carrier Proteins
• Lipoxins
• Multiprotein Complexes
• Naphthyridines
• Prostaglandins
• RICTOR protein, human
• Rapamycin-Insensitive Companion of mTOR Protein
• TSC2 protein, human
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• lipoxin A4
• Estradiol
• Cyclooxygenase 2
• Mechanistic Target of Rapamycin Complex 2
• TOR Serine-Threonine Kinases
• Aspirin

Topics

• Analysis of Variance
• Animals
• Aspirin (pharmacology)
• Breath Tests
• Carcinogenesis (metabolism)
• Carrier Proteins (genetics)
• Cell Proliferation (drug effects)
• Cyclooxygenase 2 (metabolism)
• Estradiol (metabolism)
• Female
• Gene Expression Regulation, Enzymologic (drug effects, physiology)
• Gene Knockdown Techniques
• Humans
• Immunoblotting
• Immunohistochemistry
• Lipoxins (analysis)
• Lymphangioleiomyomatosis (metabolism)
• Mechanistic Target of Rapamycin Complex 2
• Metabolomics
• Mice
• Mice, SCID
• Microscopy, Confocal
• Multiprotein Complexes (metabolism)
• Naphthyridines (pharmacology)
• Prostaglandins (biosynthesis, blood)
• Rapamycin-Insensitive Companion of mTOR Protein
• Real-Time Polymerase Chain Reaction
• TOR Serine-Threonine Kinases (metabolism)
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (deficiency)