Chen Xiaodong, Zhou Huanjiao Jenny, Huang Qunhua, Lu Lin, Min Wang
Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, 10 Amistad St., New Haven, CT 06520.
Anticancer Agents Med Chem. 2014;14(7):946-54. doi: 10.2174/1871520614666140610102651.
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.
金诺芬是一种最初开发用于治疗类风湿性关节炎的金化合物。最近的数据表明，金诺芬在治疗其他炎症性和增殖性疾病方面具有前景。然而，金诺芬的作用机制尚未明确。在本研究中，我们确定血管内皮生长因子受体-3（VEGFR3），一种对血管生成和淋巴管生成至关重要的内皮细胞（EC）表面受体，为金诺芬的新靶点。在原代EC和EC细胞系中，金诺芬均以剂量依赖性方式诱导VEGFR3下调。高剂量（≥1µM）的金诺芬会降低细胞存活蛋白硫氧还蛋白还原酶（TrxR2）、TrxR2依赖性的Trx2和转录因子NF-κB，而增加应激信号p38MAPK，导致EC凋亡。然而，低剂量（≤0.5µM）的金诺芬特异性诱导VEGFR3下调以及VEGFR3介导的EC增殖和迁移，这是体内淋巴管生成所需的两个关键步骤。从机制上讲，我们表明金诺芬诱导的VEGFR3下调被抗氧化剂N-乙酰-L-半胱氨酸（NAC）和溶酶体抑制剂氯喹阻断，但被蛋白酶体抑制剂MG132促进。这些结果表明，金诺芬通过溶酶体依赖性途径诱导VEGFR3降解。金诺芬可能是治疗诸如淋巴水肿和癌症转移等淋巴管生成依赖性疾病的有效治疗剂。
