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The JAK2/STAT3 pathway inhibitor, AG490, suppresses the abnormal behavior of keloid fibroblasts in vitro.

ABSTRACT: AG490 is a selective inhibitor of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. The present study examined its effects on the abnormal behavior of human keloid fibroblasts (HKFs) and evaluated its potential use in the treatment of keloids. Human normal fibroblasts (HNFs) and HKFs were treated with increasing concentrations of AG490. The proliferation of HNFs and HKFs was inhibited by AG490 in both a time? and concentration?dependent manner by increasing apoptosis and inducing G1 cell cycle arrest. The downregulation of cyclin D1 and connective tissue growth factor (CTGF) expression was associated with a decrease in STAT3 expression in response to AG490. The effects of AG490 on TGF???stimulated fibroblasts, including HNFs, HKFs and hypertrophic scar fibroblasts (HSFs) were also evaluated. The TGF??1?stimulated excessive proliferation and CTGF production were markedly inhibited by the application of AG490 in the HNFs, HSFs and HKFs. In addition, the STAT3?specific decoy oligodeoxynucleotides (SODNs) were transfected into HKFs. The invasive ability of the SODN?transfected HKFs was determined and the expression of extracellular matrix components was quantified. Similarly, SODNs blocked the constitutive activation of STAT3. SODNs inhibited the invasion and progression of HKFs, possibly via the upregulation of the expression of tissue inhibitor of metalloproteinase?2 (TIMP?2), and the downregulation of the expression of matrix metalloproteinase?2 (MMP?2) and vascular endothelial growth factor (VEGF). On the whole, the findings of the present study demonstrate that STAT3?specific elimination, such as the application of AG490 and decoy ODNs, may serve as promising therapeutic strategies for the treatment of keloids.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC7255460 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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The JAK2/STAT3 pathway inhibitor, AG490, suppresses the abnormal behavior of keloid fibroblasts in vitro.

Zhou Ying Y Sun Yuexin Y Hou Wenjun W Ma Liwen L Tao Yue Y Li Dan D Xu Cui C Bao Jun J Fan Weixin W

International journal of molecular medicine 20200429 1

AG490 is a selective inhibitor of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. The present study examined its effects on the abnormal behavior of human keloid fibroblasts (HKFs) and evaluated its potential use in the treatment of keloids. Human normal fibroblasts (HNFs) and HKFs were treated with increasing concentrations of AG490. The proliferation of HNFs and HKFs was inhibited by AG490 in both a time‑ and concentration‑dependent manne ...[more]

PMID: 32377718

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Project description:BackgroundFibroblast-like synoviocytes (FLS) have cancer cell-like characteristics, such as abnormal proliferation and resistance to apoptosis, and play a pathogenic role in rheumatoid arthritis (RA). Hyperproliferation of RA-FLS that can be triggered by the activation of interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling destructs cartilage and bone in RA patients. Chrysoeriol is a flavone found in medicinal herbs such as Chrysanthemi Indici Flos (the dried capitulum of Chrysanthemum indicum L.). These herbs are commonly used in treating RA. Chrysoeriol has been shown to exert anti-inflammatory effects and inhibit STAT3 signaling in our previous studies. This study aimed to determine whether chrysoeriol inhibits hyperproliferation of RA-FLS, and whether inhibiting STAT3 signaling is one of the underlying mechanisms.MethodsIL-6/soluble IL-6 receptor (IL-6/sIL-6R)-stimulated RA-FLS were used to evaluate the effects of chrysoeriol. CCK-8 assay and crystal violet staining were used to examine cell proliferation. Annexin V-FITC/PI double staining was used to detect cell apoptosis. Western blotting was employed to determine protein levels.ResultsChrysoeriol suppressed hyperproliferation of, and evoked apoptosis in, IL-6/sIL-6R-stimulated RA-FLS. The apoptotic effect of chrysoeriol was verified by its ability to cleave caspase-3 and caspase-9. Mechanistic studies revealed that chrysoeriol inhibited activation/phosphorylation of Janus kinase 2 (JAK2, Tyr1007/1008) and STAT3 (Tyr705); decreased STAT3 nuclear level and down-regulated protein levels of Bcl-2 and Mcl-1 that are transcriptionally regulated by STAT3. Over-activation of STAT3 significantly diminished anti-proliferative effects of chrysoeriol in IL-6/sIL-6R-stimulated RA-FLS.ConclusionsWe for the first time demonstrated that chrysoeriol suppresses hyperproliferation of RA-FLS, and suppression of JAK2/STAT3 signaling contributes to the underlying mechanisms. This study provides pharmacological and chemical justifications for the traditional use of chrysoeriol-containing herbs in treating RA, and provides a pharmacological basis for developing chrysoeriol into a novel anti-RA agent.

Dataset Information

The JAK2/STAT3 pathway inhibitor, AG490, suppresses the abnormal behavior of keloid fibroblasts in vitro.

Publications

The JAK2/STAT3 pathway inhibitor, AG490, suppresses the abnormal behavior of keloid fibroblasts in vitro.

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