The <scp>JAK</scp>2/<scp>STAT</scp>3 pathway is involved in the anti‐melanoma effects of atractylenolide I

Fu, Xiu‐Qiong; Chou, Ji‐Yao; Li, Ting; Zhu, Peili; Li, Jun‐Kui; Yin, Chang-Cheng; Su, Tao; Guo, Hui; Lee, Kin-Wah; Hossen, Muhammad Jahangir; Chou, Gui‐Xin; Yu, Zhi‐Ling

doi:10.1111/exd.13454

Cited by 37 publications

(29 citation statements)

References 9 publications

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“…JAK2 is a well-known upstream regulator of STAT3 activation in cancer cells (Bowman et al, 2000), and the JAK2/STAT3 pathway has been shown to alter the expression of key oncogenes and tumor suppressor genes to enhance the growth, survival, and metastasis of CRC cells (Xiong et al, 2008). Previous studies have reported that AT-I can inhibit JAK2 activation, indicating that the AT-I-induced downregulation of STAT3 phosphorylation is associated with changes in JAK2 (Fu et al, 2018). Consistent with these findings, we also found that AT-I can markedly reduce JAK2 phosphorylation in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells

Wang

Liu

et al. 2020

Front. Pharmacol.

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Colorectal cancer (CRC) is the third most common cancer worldwide and is associated with a poor clinical outcome and survival. Therefore, the development of novel therapeutic agents for CRC is imperative. Atractylenolide I (AT-I) is a sesquiterpenoid lactone derivative of Rhizoma Atractylodis macrocephalae that exhibits diverse biological activities, including anti-cancer activities. However, the effects and potential mechanism of AT-I in CRC have yet to be fully elucidated. In this study, we aimed to examine the anti-cancer properties of AT-I and the associated functional mechanisms in vitro and in vivo. We found that AT-I treatment significantly suppressed the viability of CRC cell lines and inhibited colony formation, but to a lesser extent in NCM460 cells. Annexin V/PI staining showed that AT-I induced apoptosis in CRC cells, accompanied by increased caspase-3 and PARP-1 cleavage, enhanced expression of Bax, and reduced expression of Bcl-2. Furthermore, AT-I blocked cell glycolysis by inhibiting both glucose uptake and lactate production in CRC cells, and specifically downregulated the expression of the rate-limiting glycolytic enzyme HK2. In contrast, it had no discernable effects on the glycolytic enzymes PFK and PKM2. A mechanistic study revealed that AT-1 negatively regulates STAT3 phosphorylation through direct interaction with JAK2, thereby inhibiting its activation. Moreover, restoring the expression of STAT3 reversed the effect of AT-I on apoptosis and glycolysis in CRC cells. In vivo results revealed that AT-I significantly suppressed tumor growth in HCT116-xenografted mice. Collectively, our findings indicate that the anticancer activity of AT-I in CRC is associated with the induction of apoptosis and suppression of glycolysis in CRC cells, via the disruption of JAK2/STAT3 signaling. Our preliminary experimental data indicate that AT-I may have applications as a promising candidate for the treatment of CRC.

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Section: Discussionmentioning

confidence: 99%

Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells

Wang

Liu

et al. 2020

Front. Pharmacol.

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“…AT-I is a novel TLR4-antagonizing agent [20], and it exerted anti-tumor effects on colorectal cancer, bladder cancer and melanoma [17][18][19], then we investigated whether it could suppress tumorigenesis in breast cancer via inhibiting TLR4/NF-κB pathway. Firstly, we found that AT-I could inhibit cell growth, proliferation, migration and invasion, and induce apoptosis in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…Rhizoma Atractylodis Macrocephalae, one of the traditional Chinese crude materials, had signi cant gastrointestinal tract protective, neuroprotective and immunomodulatory activities [13], and numerous lines of evidence showed that it also exerted anti-tumor, anti-in ammatory and antioxidant effects [13,14]. Atractylenolide I (AT-I), the major bioactive component from Rhizoma Atractylodes Macrocephalae, also had multiple therapeutic activities including anti-in ammatory [15,16] and anti-tumor effects [17][18][19]. Speci cally, AT-I could ameliorate LPS-induced lung damages in mouse model [15], and suppressed LPS-induced NO release and diminished pro-in ammatory cytokines levels in BV-2 cells [16].…”

Section: Introductionmentioning

confidence: 99%

“…Speci cally, AT-I could ameliorate LPS-induced lung damages in mouse model [15], and suppressed LPS-induced NO release and diminished pro-in ammatory cytokines levels in BV-2 cells [16]. AT-I had the anti-tumor effects against many cancers, such as colorectal cancer [17], non-small cell lung cancer [18] and melanoma [19], and it also had a binding site similar to LPS and served as a novel TLR4antagonizing agent [20]. Moreover, a randomized pilot study of AT-I on gastric cancer cachexia patients showed that AT-I could inhibit pro-in ammatory cytokines and proteolysis-inducing factor (PIF) proteolysis, and then alleviating symptoms of gastric cancer cachexia patients [21].…”

Section: Introductionmentioning

confidence: 99%

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Atractylenolide-I suppresses tumorigenesis of breast cancer by inhibiting toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway

Long

Lin

Zhang

et al. 2020

Preprint

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Background: Toll-like receptor 4 (TLR4) is an essential sensor related to tumorigenesis, and overexpression of TLR4 in human tumors often correlates with poor prognosis. Atractylenolide I (AT-I) is a major bioactive component from Rhizoma Atractylodes Macrocephalae. Emerging evidence suggests that AT-I exerts anti-tumor effects on various cancers such as colorectal cancer, bladder cancer and melanoma. Nevertheless, the effects of AT-I on mammary tumorigenesis remain unclear.Methods: In order to ascertain the correlation of TLR4/NF-κB pathway with breast cancer, the expression of TLR4 and NF-κB in normal breast tissues and cancer tissues with different TNM-stages was detected by human tissue microarray (TMA) and immunohistochemistry technology. The effects of AT-I on tumorigenesis were investigated by cell viability, colony formation, apoptosis, migration and invasion assays in two breast cancer cells (MCF-7 and MDA-MB-231), and N-Nitroso-N-methylurea (NMU) induced rat breast cancer models were developed to evaluate the anti-tumor effects of AT-I in vivo. The possible underlying mechanisms were further explored by western blot and ELISA assays after a series of LPS treatment and TLR4 knockdown experiments.Results：We found that TLR4 and NF-κB were significantly up-regulated in breast cancer tissues, and was correlated with advanced TNM-stages. AT-I could inhibit TLR4 mediated NF-κB signaling pathway and decrease NF-κB-regulated cytokines in breast cancer cells, thus inhibiting cell proliferation, migration and invasion, and inducing apoptosis of breast cancer cells. Furthermore, AT-I could inhibit NMU-induced rat mammary tumor progression through TLR4/NF-κB pathway.Conclusions: Our findings demonstrated that TLR4 and NF-κB were over expressed in breast cancer, and AT-I could suppress tumorigenesis of breast cancer via inhibiting TLR4-mediated NF-κB signaling pathway.

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“…Moreover, ursolic acid in GRR had a strong effect on inducing apoptosis through JAK2/STAT3 in colorectal cancer cells [36]. Atractylenolide I could induce apoptosis in bladder cancer cells by apoptotic pathway, cell cycle progression and PI3K/Akt/mTOR signaling pathway [37], and reduce viability, induced apoptosis and inhibited migration of melanoma cells [17]. Indirubin in IN inhibited JAK/STAT3 to promote apoptosis in human pancreatic cancer cells [38].…”

Section: Molecular Dockingmentioning

confidence: 99%

Network Pharmacology and Molecular docking Analysis on Mechanisms and Molecular Targets of LongChaiJiangXue Formula for Treatment of Polycythemia Vera

Ming¹,

Zhu²,

Li³

et al. 2020

Preprint

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Background: LongChaiJiangXue formula (LCJX) has the effect of not only clearing up excessive erythrocytes but also relieving clinical symptoms of Polycythemia vera (PV). Material/Methods: The chemical constitution of LCJX was identified from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP). Seven hundred and fifty-nine targets were identified and a total of 248 targets were screened out after discarding duplication and genes without any ID in databases. GeneCards database, OMIM database, and GEO database were searched for differential expression genes. The network was built by Cytoscape (3.7.2) software and the protein-protein interaction (PPI) networks of PV and LCJX were merged by https://string-db.org . Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment was processed by the R platform. The molecular docking technology was used to further analyze the intense of the assosiation of the compounds and targets. Results: 73 compounds of LCJX were chosen as the candidate active compounds. The compound-targets network contained 105 nods and 216 edges that presented the interaction of agents and targets. The PPI network of LCJX targets involved 59 nodes and 168 edges. The network showed that the key nodes were concentrated in signal transducer and activator of transcription-3(STAT-3), interleukin-6(IL-6), Janus kinase 2(JAK2), and vascular endothelial growth factor-A(VEGFA). The most enriched terms in the GO analysis in the GO biological processes(BP) were reactive oxygen species metabolic process, response to lipopolysaccharide, and response to oxidative stress. According to GO molecular functions(MF), the central nodes were generally enriched in cytokine receptor binding, cytokine activity, and heme binding. Regarding the GO cell components(CC), the terms included vesicle lumen, cytoplasmic vesicle lumen, and secretory granule lumen. In light of the KEGG enrichment analysis, the Hepatitis B, AGE-RAGE signaling pathway in diabetic complications, Kaposi sarcoma-associated herpesvirus infection, measles, Human cytomegalovirus infection, and JAK-STAT signaling pathway were significantly enriched. The molecular docking technology found that puerarin and saikosaponin A had relative stronger affinity with VEGFA, HIF-1A, JAK2 and STAT3 than other compounds in terms of the binding free energy. Conclusions: The effect of LCJX on PV is achieved through a series of complex mechanisms. Network pharmacology and molecular docking are powerful tools to reveal the effect of compound Chinese medicine on the disease.

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The JAK2/STAT3 pathway is involved in the anti‐melanoma effects of atractylenolide I

Cited by 37 publications

References 9 publications

Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells

Atractylenolide I Induces Apoptosis and Suppresses Glycolysis by Blocking the JAK2/STAT3 Signaling Pathway in Colorectal Cancer Cells

Atractylenolide-I suppresses tumorigenesis of breast cancer by inhibiting toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway

Network Pharmacology and Molecular docking Analysis on Mechanisms and Molecular Targets of LongChaiJiangXue Formula for Treatment of Polycythemia Vera

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