title: Novel action and mechanism of auranofin in inhibition of vascular endothelial growth factor receptor-3-dependent lymphangiogenesis.
abstract: Auranofin is a gold compound initially developed for the treatment of rheumatoid arthritis. Recent data suggest that auranofin has promise in the treatment of other inflammatory and proliferative diseases. However, the mechanisms of action of auranofin have not been well defined. In the present study, we identify vascular endothelial growth factor receptor-3 (VEGFR3), an endothelial cell (EC) surface receptor essential for angiogiogenesis and lymphangiogenesis, as a novel target of auranofin. In both primary EC and EC cell lines, auranofin induces downregulation of VEGFR3 in a dose-dependent manner. Auranofin at high doses (≥1 µM) decreases cellular survival protein thioredoxin reductase (TrxR2), TrxR2-dependent Trx2 and transcription factor NF-κB whereas increases stress signaling p38MAPK, leading to EC apoptosis. However, auranofin at low doses (≤0.5 µM) specifically induces downregulation of VEGFR3 and VEGFR3-mediated EC proliferation and migration, two critical steps required for in vivo lymphangiogenesis. Mechanistically, we show that auranofin-induced VEGFR3 downregulation is blocked by antioxidant N-acetyl-L-cysteine (NAC) and lysosome inhibitor chloroquine, but is promoted by proteasomal inhibitor MG132. These results suggest that auranofin induces VEGFR3 degradation through a lysosome-dependent pathway. Auranofin may be a potent therapeutic agent for the treatment of lymphangiogenesis-dependent diseases such as lymphedema and cancer metastasis.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Chen
authors.forename: Huanjiao Jenny
authors.initials: HJ
authors.lastname: Zhou
authors.forename: Qunhua
authors.initials: Q
authors.lastname: Huang
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520. Wang.Min@Yale.Edu.
authors.forename: Wang
authors.initials: W
authors.lastname: Min
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001310:Auranofin / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects*; D008247:Lysosomes / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D001310:Auranofin; D013880:Thioredoxin-Disulfide Reductase; D040321:Vascular Endothelial Growth Factor Receptor-3; D048308:Mitogen-Activated Protein Kinase 14