Peroxiredoxin 1 stimulates endothelial cell expression of VEGF via TLR4 dependent activation of HIF-1α.

Abstract

Chronic inflammation leads to the formation of a pro-tumorigenic microenvironment that can promote tumor development, growth and differentiation through augmentation of tumor angiogenesis. Prostate cancer (CaP) risk and prognosis are adversely correlated with a number of inflammatory and angiogenic mediators, including Toll-like receptors (TLRs), NF-κB and vascular endothelial growth factor (VEGF). Peroxiredoxin 1 (Prx1) was recently identified as an endogenous ligand for TLR4 that is secreted from CaP cells and promotes inflammation. Inhibition of Prx1 by CaP cells resulted in reduced expression of VEGF, diminished tumor vasculature and retarded tumor growth. The mechanism by which Prx1 regulates VEGF expression in normoxic conditions was investigated in the current study. Our results show that incubation of mouse vascular endothelial cells with recombinant Prx1 caused increases in VEGF expression that was dependent upon TLR4 and required hypoxia inducible factor-1 (HIF-1) interaction with the VEGF promoter. The induction of VEGF was also dependent upon NF-κB; however, NF-κB interaction with the VEGF promoter was not required for Prx1 induction of VEGF suggesting that NF-κB was acting indirectly to induce VEGF expression. The results presented here show that Prx1 stimulation increased NF-κB interaction with the HIF-1α promoter, leading to enhanced promoter activity and increases in HIF-1α mRNA levels, as well as augmented HIF-1 activity that resulted in VEGF expression. Prx1 induced HIF-1 also promoted NF-κB activity, suggesting the presence of a positive feedback loop that has the potential to perpetuate Prx1 induction of angiogenesis. Strikingly, inhibition of Prx1 expression in CaP was accompanied with reduced expression of HIF-1α. The combined findings of the current study and our previous study suggest that Prx1 interaction with TLR4 promotes CaP growth potentially through chronic activation of tumor angiogenesis.

• Authors: Jonah R Riddell, Patricia Maier, Stephanie N Sass, Michael T Moser, Barbara A Foster, Sandra O Gollnick
• Journal: PloS one (PLoS One) Vol. 7 Issue 11 Pg. e50394 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23185615 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Hif1a protein, mouse
• Homeodomain Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• NF-kappa B
• Prrx1 protein, mouse
• RNA, Small Interfering
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse

Topics

• Animals
• Cell Line, Tumor
• Endothelium, Vascular (immunology, metabolism, pathology)
• Gene Expression Regulation
• Homeodomain Proteins (antagonists & inhibitors, genetics, immunology, pharmacology)
• Human Umbilical Vein Endothelial Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, immunology)
• Male
• Mice
• Mice, SCID
• NF-kappa B (genetics, immunology)
• Neoplasm Transplantation
• Neovascularization, Pathologic
• Promoter Regions, Genetic
• Prostatic Neoplasms (blood supply, genetics, immunology, pathology)
• Protein Binding
• RNA, Small Interfering (genetics)
• Signal Transduction
• Toll-Like Receptor 4 (genetics, immunology)
• Vascular Endothelial Growth Factor A (genetics, immunology)