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Novel action and mechanism of auranofin in inhibition of vascular endothelial growth factor receptor-3-dependent lymphangiogenesis.
Anticancer Agents Med Chem. 2014; 14(7):946-54.AA

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+Show Affiliations

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableInterdepartmental 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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24913775

Citation

Chen, Xiaodong, et al. "Novel Action and Mechanism of Auranofin in Inhibition of Vascular Endothelial Growth Factor Receptor-3-dependent Lymphangiogenesis." Anti-cancer Agents in Medicinal Chemistry, vol. 14, no. 7, 2014, pp. 946-54.
Chen X, Zhou HJ, Huang Q, et al. Novel action and mechanism of auranofin in inhibition of vascular endothelial growth factor receptor-3-dependent lymphangiogenesis. Anticancer Agents Med Chem. 2014;14(7):946-54.
Chen, X., Zhou, H. J., Huang, Q., Lu, L., & Min, W. (2014). Novel action and mechanism of auranofin in inhibition of vascular endothelial growth factor receptor-3-dependent lymphangiogenesis. Anti-cancer Agents in Medicinal Chemistry, 14(7), 946-54.
Chen X, et al. Novel Action and Mechanism of Auranofin in Inhibition of Vascular Endothelial Growth Factor Receptor-3-dependent Lymphangiogenesis. Anticancer Agents Med Chem. 2014;14(7):946-54. PubMed PMID: 24913775.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel action and mechanism of auranofin in inhibition of vascular endothelial growth factor receptor-3-dependent lymphangiogenesis. AU - Chen,Xiaodong, AU - Zhou,Huanjiao Jenny, AU - Huang,Qunhua, AU - Lu,Lin, AU - Min,Wang, PY - 2014/05/03/received PY - 2014/06/06/revised PY - 2014/06/08/accepted PY - 2014/6/11/entrez PY - 2014/6/11/pubmed PY - 2015/6/3/medline SP - 946 EP - 54 JF - Anti-cancer agents in medicinal chemistry JO - Anticancer Agents Med Chem VL - 14 IS - 7 N2 - 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. SN - 1875-5992 UR - https://www.unboundmedicine.com/medline/citation/24913775/Novel_action_and_mechanism_of_auranofin_in_inhibition_of_vascular_endothelial_growth_factor_receptor_3_dependent_lymphangiogenesis_ L2 - http://www.eurekaselect.com/122670/article DB - PRIME DP - Unbound Medicine ER -