Document Detail


Dehydroepiandrosterone inhibits glucose flux through the pentose phosphate pathway in human and mouse endometrial stromal cells, preventing decidualization and implantation.
MedLine Citation:
PMID:  21680659     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Endometrial stromal cells (ESC) must undergo a hormone-driven differentiation to form decidual cells as a requirement of proper embryo implantation. Recent studies from our laboratory have demonstrated that decidualizing cells require glucose transporter 1 expression and an increase in glucose use to complete this step. The present study focuses on the glucose-dependent molecular and metabolic pathways, which are required by ESC for decidualization. Inhibition of glycolysis had no effect on decidualization. However, blockade of the pentose phosphate pathway (PPP) with pharmacologic inhibitors 6-aminonicotinamide or dehydroepiandrosterone (DHEA), and short hairpin RNA-mediated knockdown of glucose-6-phosphate dehydrogenase, the rate-limiting step in the PPP, both led to strong decreases in decidual marker expression in vitro and decreased decidualization in vivo. Additionally, the studies demonstrate that inhibition is due, at least in part, to ribose-5-phosphate depletion, because exogenous nucleoside administration restored decidualization in these cells. The finding that PPP inhibition prevents decidualization of ESC is novel and clinically important, because DHEA is an endogenous hormone produced by the adrenal glands and elevated in a high proportion of women who have polycystic ovary syndrome, the most common endocrinopathy in reproductive age women. Together, this data suggest a mechanistic link between increased DHEA levels, use of glucose via the PPP, and pregnancy loss.
Authors:
Antonina I Frolova; Kathleen O'Neill; Kelle H Moley
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-06-16
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  25     ISSN:  1944-9917     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-29     Completed Date:  2011-11-21     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1444-55     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
6-Aminonicotinamide / pharmacology
Animals
Biological Transport / drug effects
Cell Proliferation / drug effects
Decidua / cytology*,  drug effects,  metabolism*
Dehydroepiandrosterone / pharmacology*
Deoxyribonucleosides / pharmacology
Embryo Implantation / drug effects*
Female
Glucose / metabolism*
Glycolysis / drug effects
Humans
Mice
Models, Biological
Pentose Phosphate Pathway / drug effects*
Pregnancy
Ribonucleosides / pharmacology
Stromal Cells / cytology,  drug effects,  metabolism
Grant Support
ID/Acronym/Agency:
F30 DK083224/DK/NIDDK NIH HHS; P30 DK056341/DK/NIDDK NIH HHS; P30 DK056341-11/DK/NIDDK NIH HHS; R01 HD065435/HD/NICHD NIH HHS; R01 HD065435/HD/NICHD NIH HHS
Chemical
Reg. No./Substance:
0/Deoxyribonucleosides; 0/Ribonucleosides; 329-89-5/6-Aminonicotinamide; 459AG36T1B/Dehydroepiandrosterone; IY9XDZ35W2/Glucose
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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