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Isoliquiritigenin suppresses human T Lymphocyte activation via covalently binding cysteine 46 of I?B kinase.

ABSTRACT: The efficacious practice of precision personalized medicine requires a more exact understanding of the molecular mechanisms of drug, hence then it is necessary to identify the binding site of the drugs derived from natural sources. In the study, we investigated the suppressive effect and underlying mechanism of isoliquiritigenin (2',4',4-trihydroxychalcone; ILG), a phyto-flavonoid, on human T lymphocyte activation in vitro and in vivo. The results showed that ILG dose-dependently suppressed human T cell activation via suppressing I?B? phosphorylation and degradation, NF-?B nuclear translocation and IKK? activity. Molecular docking results predicted that cysteine 46 (Cys-46) is probably the binding site of ILG on IKK?, and this prediction has been validated by competition assay and kinase assay. To further verify the binding site of this compound in vivo, IKK?C46A transgenic (IKK?C46A) mice were generated. We found that ILG had a less potent immune-suppressive effect in homozygous IKK?C46A mice than IKK? wild type (IKK? wt) littermates with the delay-type hypersensitivity (DTH), suggesting that ILG cannot significantly suppress the inflammation due to the mutation of Cys-46 in the transgenic mice. Collectively, our findings indicate that the ILG inhibited T cell activation in vivo and in vitro via directly binding to IKK? Cys46.

SUBMITTER: Yan F

PROVIDER: S-EPMC5470962 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Isoliquiritigenin suppresses human T Lymphocyte activation via covalently binding cysteine 46 of IκB kinase.

Yan Fenggen F Yang Fen F Wang Rui R Yao Xiao Jun XJ Bai Liping L Zeng Xing X Huang JiaJun J Wong Vincent Kam Wai VKW Lam Christopher Wai Kei CWK Zhou Hua H Su Xiaohui X Liu Juan J Li Ting T Liu Liang L

Oncotarget 20170501 21

The efficacious practice of precision personalized medicine requires a more exact understanding of the molecular mechanisms of drug, hence then it is necessary to identify the binding site of the drugs derived from natural sources. In the study, we investigated the suppressive effect and underlying mechanism of isoliquiritigenin (2',4',4-trihydroxychalcone; ILG), a phyto-flavonoid, on human T lymphocyte activation in vitro and in vivo. The results showed that ILG dose-dependently suppressed huma ...[more]

PMID: 27626700

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Project description:BackgroundIsoliquiritigenin (ISL), a natural flavonoid isolated from the root of licorice (Glycyrrhiza uralensis), has shown various pharmacological properties including anti-oxidant, anti-inflammatory and anti-cancer activities. MicroRNAs (miRNAs), a class of small non-coding RNAs, have been reported as post-transcriptional regulators with altered expression levels in melanoma. This study aims to investigate the anti-melanoma effect of ISL and its potential mechanism.MethodsWe investigated the effect of ISL on the proliferation and apoptosis of melanoma cell lines with functional assays, such as CCK-8 assay, colony formation assay and flow cytometry. The protein level of apoptosis related genes were measured by western blotting. High-throughput genome sequencing was used for screening differentially expressed miRNAs of melanoma cell lines after the treatment of ISL. We performed functional assays to determine the oncogenic role of miR-301b, the most differentially expressed miRNA, and its target gene leucine rich repeats and immunoglobulin like domains 1 (LRIG1), confirmed by bioinformatic analysis, luciferase reporter assay, western blotting and immunohistochemical assay in melanoma. Immunocompromised mouse models were used to determine the role of miR-301b and its target gene in melanoma tumorigenesis in vivo. The relationship between miR-301b and LRIG1 was further verified in GEO data set and tissue specimens.ResultsFunctional assays indicated that ISL exerted significant growth inhibition and apoptosis induction on melanoma cells. MiR-301b is the most differentially expressed miRNA after the treatment of ISL and significantly downregulated. The suppressive effect of ISL on cell growth is reversed by ectopic expression of miR-301b. Intratumorally administration of miR-301b angomir enhances the inhibitory effect of ISL on tumor growth in vivo. Bioinformatic analysis showed that miR-301b may target LRIG1, miR-301b suppresses the luciferase activity of reporter constructs containing 3'UTR of LRIG1 as well as the expression level of LRIG1. And the anti-cancer effect of ISL is mitigated when LRIG1 is silenced in vivo and in vitro. Analysis of the melanoma samples obtained from patients shows that LRIG1 is negatively correlated with miR-301b.ConclusionsISL may inhibit the proliferation of melanoma cells by suppressing miR-301b and inducing its target LRIG1.

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Isoliquiritigenin suppresses human T Lymphocyte activation via covalently binding cysteine 46 of I?B kinase.

Publications

Isoliquiritigenin suppresses human T Lymphocyte activation via covalently binding cysteine 46 of IκB kinase.

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