Accession Number:

ADA591414

Title:

Targeting Estrogen-Induced COX-2 Activity in Lymphangioleiomyomatosis (LAM)

Descriptive Note:

Annual rept. 15 Sep 2012-14 Sep 2013

Corporate Author:

BRIGHAM AND WOMENS HOSPITAL BOSTON MA

Personal Author(s):

Report Date:

2013-10-01

Pagination or Media Count:

43.0

Abstract:

Lymphangioleiomyomatosis LAM is a progressive 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 an estradiolenhanced 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 also increased at baseline in TSC2-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 TSC2-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.

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE