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NADPH oxidase 4 (NOX4) derived ROS mediate fibroblast to myofibroblast transdifferentiation in the diseased prostatic stroma
Author(s) -
Sampson Natalie,
Plas Eugen,
Berger Peter
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.702.1
Subject(s) - nox4 , transdifferentiation , myofibroblast , cancer research , microbiology and biotechnology , mapk/erk pathway , stromal cell , chemistry , lncap , biology , nadph oxidase , reactive oxygen species , phosphorylation , medicine , cancer cell , fibrosis , cancer , stem cell , genetics
Benign prostatic hyperplasia (BPH) and prostate cancer (PCa), two of the most common proliferative disorders affecting elderly males, are associated with stromal remodeling in particular fibroblast to myofibroblast transdifferentiation, which promotes disease progression via elevated secretion of mitogenic cytokines and growth factors. Microarrays of primary prostatic stromal fibroblasts (PrSCs) undergoing transdifferentiation revealed a pro‐oxidant shift in intracellular redox homeostasis with upregulation of NOX4 and downregulation of reactive oxygen species (ROS) scavenging enzymes. Consistently, transdifferentiation was associated with elevated ROS production, which temporally correlated with NOX4 induction prior to induction of transdifferentiation markers, αsmooth muscle cell actin (α‐SMA) and Insulin‐like growth factor binding protein 3 (IGFBP3). Inhibition via the antioxidant selenite or NOX4 knockdown indicated an essential role of NOX4‐derived ROS in driving transdifferentiation. Time course assays showed biphasic ERK phosphorylation with late phase phosphorylation being ROS dependent. ROS inhibition prior to late phase ERK phosphorylation attenuated not only ERK phosphorylation but also inhibited α‐SMA induction. Consistently, an ERK inhibitor prevented IGFBP3 induction. These data provide first evidence that NOX4‐derived ROS drives stromal remodeling associated with prostatic disease, at least in part via redox‐regulation of ERK phosphorylation and indicate potential therapeutic benefit of NOX4 inhibition.