Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 336, Issue -, Pages 31-39Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2017.10.004
Keywords
Kaempferol glucopyranoside; Saussurea stella; Interferon; JAK/STAT; SOCS3
Categories
Funding
- National Natural Science Foundation of China [21561142003, 21672207]
- Science & Technology Department of Sichuan Province [2016HH0073, 2016JZ0022]
- CAS-TWAS President's PhD Fellowship Program, Chinese Academy of Sciences President's International Fellowship Initiative [2015PB061]
- National New Drug Innovation Major Project of China [2017ZX09101003-001-006]
- Thailand Research Fund [DBG5980003]
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Suppressor of cytokine signaling 3 (SOCS3) is a key negative regulator of type I interferon (IFN alpha/beta) signaling. Inhibition of SOCS3 by small molecules may be a new strategy to enhance the efficacy of type I IFN and reduce its side effects. We established a cell-based screening assay using human hepatoma HepG2 cells stably transfected with a plasmid wherein the luciferase reporter activity was propelled by interferon alpha-stimulated response element (ISRE), which is a motif specifically recognized by type I IFN-induced activation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. After screening our chemical library, 6-hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside (K6G) was identified to be a potent activator of type I IFN with EC50 value of 3.33 +/- 0.04 mu M. K6G enhanced the phosphorylation of JAK1, Tyk2, and STAT1/2 but decreased the phosphorylation of STAT3. K6G also promoted endogenous IFN-alpha-regulated genes expression. More interestingly, K6G significantly decreased the expression of SOCS3 without affecting the expression of SOCS1. Furthermore, K6G enhanced the anti-proliferative effect of IFN-alpha on hepatocellular carcinoma (HCC) cells. These results suggested that K6G potentiated the inhibitory effect of IFN-alpha on HCC cell proliferation through activation of the JAK/STAT signaling pathway by inhibiting SOCS3 expression. K6G warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-alpha/beta.
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