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Toxicol Appl Pharmacol. 2017 Dec 1;336:31-39. doi: 10.1016/j.taap.2017.10.004. Epub 2017 Oct 12.

6-Hydroxy-3-O-methyl-kaempferol 6-O-glucopyranoside potentiates the anti-proliferative effect of interferon α/β by promoting activation of the JAK/STAT signaling by inhibiting SOCS3 in hepatocellular carcinoma cells.

Author information

1
Key Laboratory of Natural Medicine and Clinical Translation, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; University of Chinese Academy of Sciences, China.
2
Key Laboratory of Natural Medicine and Clinical Translation, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; Department of Antibiotic Research & Re-evaluation, Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu 610052, China.
3
Key Laboratory of Natural Medicine and Clinical Translation, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
4
Key Laboratory of Natural Medicine and Clinical Translation, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China; Department of Chemistry, Faculty of Science and Technology, Pibulsongkram Rajabhat University, Phitsanulok, Thailand.
5
Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Ramkhamhaeng University, Bangkok 10240, Thailand.
6
Key Laboratory of Natural Medicine and Clinical Translation, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China. Electronic address: zhanggl@cib.ac.cn.
7
Key Laboratory of Natural Medicine and Clinical Translation, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China. Electronic address: wangfei@cib.ac.cn.

Abstract

Suppressor of cytokine signaling 3 (SOCS3) is a key negative regulator of type I interferon (IFN α/β) 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 α-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±0.04μM. K6G enhanced the phosphorylation of JAK1, Tyk2, and STAT1/2 but decreased the phosphorylation of STAT3. K6G also promoted endogenous IFN-α-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-α on hepatocellular carcinoma (HCC) cells. These results suggested that K6G potentiated the inhibitory effect of IFN-α 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-α/β.

KEYWORDS:

Interferon; JAK/STAT; Kaempferol glucopyranoside; SOCS3; Saussurea stella

PMID:
29031523
DOI:
10.1016/j.taap.2017.10.004
[Indexed for MEDLINE]

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