Dietary quercetin potentiates the antiproliferative effect of interferon-alpha in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase

doi:10.18632/oncotarget.22556

	Dietary quercetin potentiates the antiproliferative effect of interferon-alpha in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase
	Igbe, I; Shen, XF; Jiao, W; Qiang, Z; Deng, T; Li, S; Liu, WL; Liu, HW; Zhang, GL; Wang, F
刊名	ONCOTARGET
	2017
卷号	8 期号:69 页码:113734-113748
关键词	Quercetin Interferon Shp2 Jak Stat
DOI	10.18632/oncotarget.22556
产权排序	1
文献子类	Article
英文摘要	Type I interferons (IFN-alpha/beta) have broad and potent immunoregulatory and antiproliferative activities, which are negatively regulated by Src homology domain 2 containing tyrosine phosphatase-2 (SHP-2). Inhibition of SHP2 by small molecules may be a new strategy to enhance the effcacy of type I IFNs. Using an in vitro screening assay for new inhibitors of SHP2 phosphatase, we found that quercetin was a potent inhibitor of SHP2. Computational modeling showed that quercetin exhibited an orientation favorable to nucleophilic attack in the phosphatase domain of SHP2. Quercetin enhanced the phosphorylation of signal transducer and activator of transcription proteins 1 (STAT1) and promoted endogenous IFN-alpha-regulated gene expression. Furthermore, quercetin also sensitized the antiproliferative effect of IFN-alpha on hepatocellular carcinoma HepG2 and Huh7 cells. The overexpression of SHP2 attenuated the effect of quercetin on IFN-alpha-stimulated STAT1 phosphorylation and antiproliferative effect, whereas the inhibition of SHP2 promoted the effect of quercetin on IFN-alpha-induced STAT1 phosphorylation and antiproliferative effect. The results suggested that quercetin potentiated the inhibitory effect of IFN-alpha on cancer cell proliferation through activation of JAK/STAT pathway signaling by inhibiting SHP2. Quercetin warrants further investigation as a novel therapeutic method to enhance the efficacy of IFN-alpha/beta.
学科主题	Oncology ; Cell Biology
项目编号	天然药物和临床转化实验室
语种	英语
资助机构	This work was supported by the National Natural Science Foundation of China (No. 21561142003, 21672207, 21672205), Science & Technology Department of Sichuan Province (No. 2016JZ0022), Chinese Academy of Sciences President's International Fellowship Initiative (No. 2015PB049), the National New Drug Innovation Major Project of China (2017ZX09101003-001-006), and Research Foundation of State General Administration of The People's Republic of China for Quality Supervision and Inspection and Quarantine (No. 20151K180). ; National Natural Science Foundation of China [21561142003, 21672207, 21672205] ; This work was supported by the National Natural Science Foundation of China (No. 21561142003, 21672207, 21672205), Science & Technology Department of Sichuan Province (No. 2016JZ0022), Chinese Academy of Sciences President's International Fellowship Initiative (No. 2015PB049), the National New Drug Innovation Major Project of China (2017ZX09101003-001-006), and Research Foundation of State General Administration of The People's Republic of China for Quality Supervision and Inspection and Quarantine (No. 20151K180). ; National Natural Science Foundation of China [21561142003, 21672207, 21672205] ; Science & Technology Department of Sichuan Province [2016JZ0022] ; Science & Technology Department of Sichuan Province [2016JZ0022] ; Chinese Academy of Sciences President's International Fellowship Initiative [2015PB049] ; Chinese Academy of Sciences President's International Fellowship Initiative [2015PB049] ; National New Drug Innovation Major Project of China [2017ZX09101003-001-006] ; National New Drug Innovation Major Project of China [2017ZX09101003-001-006] ; Research Foundation of State General Administration of The People's Republic of China for Quality Supervision and Inspection and Quarantine [20151K180] ; Research Foundation of State General Administration of The People's Republic of China for Quality Supervision and Inspection and Quarantine [20151K180] ; This work was supported by the National Natural Science Foundation of China (No. 21561142003, 21672207, 21672205), Science & Technology Department of Sichuan Province (No. 2016JZ0022), Chinese Academy of Sciences President's International Fellowship Initiative (No. 2015PB049), the National New Drug Innovation Major Project of China (2017ZX09101003-001-006), and Research Foundation of State General Administration of The People's Republic of China for Quality Supervision and Inspection and Quarantine (No. 20151K180). ; National Natural Science Foundation of China [21561142003, 21672207, 21672205] ; This work was supported by the National Natural Science Foundation of China (No. 21561142003, 21672207, 21672205), Science & Technology Department of Sichuan Province (No. 2016JZ0022), Chinese Academy of Sciences President's International Fellowship Initiative (No. 2015PB049), the National New Drug Innovation Major Project of China (2017ZX09101003-001-006), and Research Foundation of State General Administration of The People's Republic of China for Quality Supervision and Inspection and Quarantine (No. 20151K180). ; National Natural Science Foundation of China [21561142003, 21672207, 21672205] ; Science & Technology Department of Sichuan Province [2016JZ0022] ; Science & Technology Department of Sichuan Province [2016JZ0022] ; Chinese Academy of Sciences President's International Fellowship Initiative [2015PB049] ; Chinese Academy of Sciences President's International Fellowship Initiative [2015PB049] ; National New Drug Innovation Major Project of China [2017ZX09101003-001-006] ; National New Drug Innovation Major Project of China [2017ZX09101003-001-006] ; Research Foundation of State General Administration of The People's Republic of China for Quality Supervision and Inspection and Quarantine [20151K180] ; Research Foundation of State General Administration of The People's Republic of China for Quality Supervision and Inspection and Quarantine [20151K180]
内容类型	期刊论文
源URL	[http://210.75.237.14/handle/351003/29200]
专题	成都生物研究所_天然产物研究
通讯作者	Wang, F (reprint author), Chinese Acad Sci, Chengdu Inst Biol, Key Lab Nat Med & Clin Translat, Chengdu, Sichuan, Peoples R China.
推荐引用方式 GB/T 7714	Igbe, I,Shen, XF,Jiao, W,et al. Dietary quercetin potentiates the antiproliferative effect of interferon-alpha in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase[J]. ONCOTARGET,2017,8(69):113734-113748.
APA	Igbe, I.,Shen, XF.,Jiao, W.,Qiang, Z.,Deng, T.,...&Wang, F .(2017).Dietary quercetin potentiates the antiproliferative effect of interferon-alpha in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase.ONCOTARGET,8(69),113734-113748.
MLA	Igbe, I,et al."Dietary quercetin potentiates the antiproliferative effect of interferon-alpha in hepatocellular carcinoma cells through activation of JAK/STAT pathway signaling by inhibition of SHP2 phosphatase".ONCOTARGET 8.69(2017):113734-113748.