Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells

DSpace/Manakin Repository

Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells

Citable link to this page

 

 
Title: Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells
Author: Li, Chenggang; Lee, Po-Shun; Sun, Yang; Gu, Xiaoxiao; Zhang, Erik; Guo, Yanan; Wu, Chin-Lee; Auricchio, Neil; Priolo, Carmen; Li, Jing; Csibi, Alfredo; Parkhitko, Andrey; Morrison, Tasha; Planaguma, Anna; Kazani, Shamsah; Israel, Elliot; Xu, Kai-Feng; Henske, Elizabeth Petri; Blenis, John; Levy, Bruce D.; Kwiatkowski, David; Yu, Jane J.

Note: Order does not necessarily reflect citation order of authors.

Citation: Li, 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.
Full Text & Related Files:
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.
Published Version: doi:10.1084/jem.20131080
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3892971/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:12717476
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters