Source:http://linkedlifedata.com/resource/pubmed/id/21273445
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
3
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pubmed:dateCreated |
2011-2-25
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pubmed:abstractText |
Stromal remodeling, in particular fibroblast-to-myofibroblast differentiation, is a hallmark of benign prostatic hyperplasia (BPH) and solid tumors, including prostate cancer (PCa). Increased local production of TGF?1 is considered the inducing stimulus. Given that stromal remodeling actively promotes BPH/PCa development, there is considerable interest in developing stromal-targeted therapies. Microarray and quantitative PCR analysis of primary human prostatic stromal cells induced to undergo fibroblast-to-myofibroblast differentiation with TGF?1 revealed up-regulation of the reactive oxygen species (ROS) producer reduced nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) and down-regulation of the selenium-containing ROS-scavenging enzymes glutathione peroxidase 3, thioredoxin reductase 1 (TXNRD1), and the selenium transporter selenoprotein P plasma 1. Consistently, NOX4 expression correlated specifically with the myofibroblast phenotype in vivo, and loss of selenoprotein P plasma 1 was observed in tumor-associated stroma of human PCa biopsies. Using lentiviral NOX4 short hairpin RNA-mediated knockdown, pharmacological inhibitors, antioxidants, and selenium, we demonstrate that TGF?1 induction of NOX4-derived ROS is required for TGF?1-mediated phosphorylation of c-jun N-terminal kinase, which in turn is essential for subsequent downstream cytoskeletal remodeling. Significantly, selenium supplementation inhibited differentiation by increasing ROS-scavenging selenoenzyme biosynthesis because glutathione peroxidase 3 and TXNRD1 expression and TXNRD1 enzyme activity were restored. Consistently, selenium depleted ROS levels downstream of NOX4 induction. Collectively, this work demonstrates that dysregulated redox homeostasis driven by elevated NOX4-derived ROS signaling underlies fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma. Further, these data indicate the potential clinical value of selenium and/or NOX4 inhibitors in preventing the functional pathogenic changes of stromal cells in BPH and PCa.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
1944-9917
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:volume |
25
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
503-15
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pubmed:meshHeading |
pubmed-meshheading:21273445-Blotting, Western,
pubmed-meshheading:21273445-Cell Differentiation,
pubmed-meshheading:21273445-Cell Line,
pubmed-meshheading:21273445-Fibroblasts,
pubmed-meshheading:21273445-Humans,
pubmed-meshheading:21273445-Immunohistochemistry,
pubmed-meshheading:21273445-Male,
pubmed-meshheading:21273445-Myofibroblasts,
pubmed-meshheading:21273445-NADPH Oxidase,
pubmed-meshheading:21273445-Oligonucleotide Array Sequence Analysis,
pubmed-meshheading:21273445-Polymerase Chain Reaction,
pubmed-meshheading:21273445-Reactive Oxygen Species,
pubmed-meshheading:21273445-Signal Transduction,
pubmed-meshheading:21273445-Transforming Growth Factor beta1
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pubmed:year |
2011
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pubmed:articleTitle |
ROS signaling by NOX4 drives fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma.
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pubmed:affiliation |
Institute of Biomedical Aging Research, Austrian Academy of Science, Rennweg 10, Innsbruck, Austria.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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