title: Decorin antagonizes the angiogenic network: concurrent inhibition of Met, hypoxia inducible factor 1α, vascular endothelial growth factor A, and induction of thrombospondin-1 and TIMP3.
abstract: Decorin, a small leucine-rich proteoglycan, inhibits tumor growth by antagonizing multiple receptor tyrosine kinases including EGFR and Met. Here, we investigated decorin during normoxic angiogenic signaling. An angiogenic PCR array revealed a profound decorin-evoked transcriptional inhibition of pro-angiogenic genes, such as HIF1A. Decorin evoked a reduction of hypoxia inducible factor (HIF)-1α and vascular endothelial growth factor A (VEGFA) in MDA-231 breast carcinoma cells expressing constitutively-active HIF-1α. Suppression of Met with decorin or siRNA evoked a similar reduction of VEGFA by attenuating downstream β-catenin signaling. These data establish a noncanonical role for β-catenin in regulating VEGFA expression. We found that exogenous decorin induced expression of thrombospondin-1 and TIMP3, two powerful angiostatic agents. In contrast, decorin suppressed both the expression and enzymatic activity of matrix metalloprotease (MMP)-9 and MMP-2, two pro-angiogenic proteases. Our data establish a novel duality for decorin as a suppressor of tumor angiogenesis under normoxia by simultaneously down-regulating potent pro-angiogenic factors and inducing endogenous anti-angiogenic agents.
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Neill
authors.forename: Hannah
authors.initials: H
authors.lastname: Painter
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.forename: Rick T
authors.initials: RT
authors.lastname: Owens
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058575:Decorin / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D058575:Decorin; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019700:Thrombospondin 1; D019717:Tissue Inhibitor of Metalloproteinase-3; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D019859:Proto-Oncogene Proteins c-met; D020782:Matrix Metalloproteinases