| A local paracrine and endocrine network involving TGFβ, Cox-2, ROS, and estrogen receptor β influences reactive stromal cell regulation of prostate cancer cell motility. | |
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MedLine Citation:
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PMID: 22593181 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The tumor microenvironment plays a critical role in supporting cancer cells particularly as they disengage from limitations on their growth and motility imposed by surrounding nonreactive stromal cells. We show here that stromal-derived androgenic precursors are metabolized by DU145 human prostate cancer (PCa) cells to generate ligands for estrogen receptor-β, which act to limit their motility through transcriptional regulation of E-cadherin. Although primary human PCa-associated fibroblasts and the human WPMY-1-reactive prostate stromal cell line maintain this inherent estrogen receptor (ER)β-dependent motility inhibitor activity, they are subverted by TGF-β1 pro-oxidant signals derived from cocultured DU145 PCa cells. Specifically, stromal-produced H(2)O(2), which requires Cox-2, acts as a second paracrine factor to inhibit ERβ activity in adjacent DU145 cells. Chromatin immunoprecipitation analysis reveals that ERβ recruitment to the E-cadherin promoter is inhibited when H(2)O(2) is present. Both neutralization of H(2)O(2) with catalase and prevention of its production by silencing Cox-2 expression in stromal cells restore the motility-suppression activity of stromal-derived ERβ ligand precursors. These data suggest that reactive stromal cells may still have a capacity to limit cancer cell motility through a local endocrine network but must be protected from pro-oxidant signals triggered by cancer cell-derived TGF-β1 to exhibit this cancer-suppressive function. |
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Authors:
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Melanie J Grubisha; M E Cifuentes; Stephen R Hammes; Donald B Defranco |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2012-05-16 |
Journal Detail:
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Title: Molecular endocrinology (Baltimore, Md.) Volume: 26 ISSN: 1944-9917 ISO Abbreviation: Mol. Endocrinol. Publication Date: 2012 Jun |
Date Detail:
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Created Date: 2012-05-21 Completed Date: 2012-09-20 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: United States |
Other Details:
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Languages: eng Pagination: 940-54 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Androgens
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metabolism Cadherins / genetics, metabolism Cell Line, Tumor Cell Movement* Coculture Techniques Cyclooxygenase 2 / genetics, metabolism* Estrogen Receptor beta / metabolism* Gene Expression Regulation, Neoplastic Humans Hydrogen Peroxide / metabolism* Intracellular Signaling Peptides and Proteins / metabolism Male Paracrine Communication Promoter Regions, Genetic Prostatic Neoplasms Reactive Oxygen Species / metabolism Signal Transduction Stromal Cells / metabolism, physiology* Transforming Growth Factor beta1 / metabolism, physiology* Tumor Microenvironment Up-Regulation |
| Grant Support | |
ID/Acronym/Agency:
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R01 DK078394/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Androgens; 0/Cadherins; 0/Estrogen Receptor beta; 0/Intracellular Signaling Peptides and Proteins; 0/Reactive Oxygen Species; 0/Transforming Growth Factor beta1; 7722-84-1/Hydrogen Peroxide; EC 1.14.99.1/Cyclooxygenase 2; EC 1.14.99.1/PTGS2 protein, human |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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