Fisetin activates Hippo pathway and JNK/ERK/AP‐1 signaling to inhibit proliferation and induce apoptosis of human osteosarcoma cells via ZAK overexpression

Fu, Chien‐Yao; Chen, Mei‐Chih; Tseng, Yan‐Shen; Chen, Ming‐Cheng; Zhou, Zhengtao; Yang, Jaw‐Ji; Lin, Yueh‐Min; Viswanadha, Vijaya Padma; Wang, Guiqing; Huang, Chih‐Yang

doi:10.1002/tox.22761

Cited by 29 publications

(25 citation statements)

References 28 publications

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“…[17][18][19] It was recently reported to have antiproliferative and apoptotic activity in various cancer cell lines, including human head and neck cancer, osteosarcoma, breast cancer, and renal cancer stem cell, suggesting that it could be used as a novel anti-cancer agent. [20][21][22][23] We previously confirmed that fisetin inhibited malignant proliferation in human OSCC by blocking the Met/Src signaling pathway. 24 However, no crucial downstream molecular targets for the anti-proliferation effect of fisetin in OSCC have yet been identified.…”

Section: Introductionmentioning

confidence: 69%

<p>Fisetin Modulates Human Oral Squamous Cell Carcinoma Proliferation by Blocking PAK4 Signaling Pathways</p>

Li¹,

Jia²,

Dai³

2020

DDDT

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Objective: Human oral squamous cell carcinoma (OSCC) is a major cause of mortality and morbidity worldwide. There is an urgent need to identify bioactive molecules and potential target genes that could inhibit carcinogenesis for OSCC therapy. Fisetin (3,7,3′,4′-tetrahydroxyflavone), a naturally occurring flavonoid, has been previously shown to have anti-proliferative activities in OSCC; however, its molecular mechanism is unknown. Methods: Colony formation, cell viability, Boyden chamber, wound healing, and tumor xenograft assays were used to detect the impact of fisetin on OSCC cells in vitro and in vivo. Western blot analysis was used to examine the corresponding protein expression. Results: Fisetin treatment significantly inhibited proliferation and promoted apoptosis by repressing PAK4 expression. Moreover, fisetin treatment attenuated cell migration by blocking PAK4 signaling pathways. In addition, the tumor xenograft showed anti-tumor growth effects of fisetin exposure in vivo. Conclusion: Fisetin may represent a potential therapeutic strategy for human OSCC by targeting PAK4 signaling pathways.

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Section: Introductionmentioning

confidence: 69%

<p>Fisetin Modulates Human Oral Squamous Cell Carcinoma Proliferation by Blocking PAK4 Signaling Pathways</p>

Li¹,

Jia²,

Dai³

2020

DDDT

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“…Fisetin and other flavonoids have been shown to regulate cell functions, i.e., regulation of vascular smooth muscle contractility [7], protecting against hepatic steatosis [8], also has beneficial effects on anti-neurodegenerative and neuroprotective function [3]. Mechanistically, fisetin could regulate cell function by affecting several important signaling pathways, including PI3K/Akt [9,10], JAK/STAT [11,12], AMPK [8,13], and the Hippo signaling pathway [14]. Furthermore, fisetin can regulate the levels of various growth factors and proinflammatory cytokines, i.e., prostaglandin E2, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-8 depending on the flavonoid structure and the cell types involved [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…A previous study reported that fisetin treatment can alter activity of Hippo signaling pathway as fisetin can upregulate expression of leucine zipper containing kinase (ZAK), a kinase in the MAP3K family, to induce the activity of Hippo pathway core-kinases, MST1/2 and LAT1/2, and mediate the activation of JNK/ERK. Activation of these kinases resulted in apoptosis of osteosarcoma cells [14]. We have recently shown that Yes-associated protein (YAP), a transcriptional coactivator that is negatively regulated by Hippo pathway core-kinases, plays a critical role in regulating adipo-osteogenic lineage differentiation of human MSCs.…”

Section: Introductionmentioning

confidence: 99%

Fisetin Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells via the Inhibition of YAP

et al. 2021

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Mesenchymal stem cells (MSCs) are self-renewal and capable of differentiating to various functional cell types, including osteocytes, adipocytes, myoblasts, and chondrocytes. They are, therefore, regarded as a potential source for stem cell therapy. Fisetin is a bioactive flavonoid known as an active antioxidant molecule that has been reported to inhibit cell growth in various cell types. Fisetin was shown to play a role in regulating osteogenic differentiation in animal-derived MSCs; however, its molecular mechanism is not well understood. We, therefore, studied the effect of fisetin on the biological properties of human MSCs derived from chorion tissue and its role in human osteogenesis using MSCs and osteoblast-like cells (SaOs-2) as a model. We found that fisetin inhibited proliferation, migration, and osteogenic differentiation of MSCs as well as human SaOs-2 cells. Fisetin could reduce Yes-associated protein (YAP) activity, which results in downregulation of osteogenic genes and upregulation of fibroblast genes. Further analysis using molecular docking and molecular dynamics simulations suggests that fisetin occupied the hydrophobic TEAD pocket preventing YAP from associating with TEA domain (TEAD). This finding supports the potential application of flavonoids like fisetin as a protein–protein interaction disruptor and also suggesting an implication of fisetin in regulating human osteogenesis.

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“…JUN is also called as transcription factor AP-1, which is a dimer composed of c-jun protein and c-fos protein family members. With the function of regulating the release of many inflammatory factors, such as IL-1 β, TNF-α, IL-6, IL-8, etc., activated AP-1 is called the third messenger of intracellular signaling, and it also plays a regulatory role in cell proliferation, differentiation, apoptosis and inflammation [24]. Lim et al [25] study found that the blocking of the signaling pathways p38 MAPK/AP-1 and JAK2/STAT1/2 can significantly reduce the release of MMP-13 in chondrocytes treated by IL-1β, thus exerting the effect of protecting cartilage degeneration [26].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacological Mechanism Research of Herba Drynariae Rhizoma-Epimedii Folium in Treating Osteoarthritis

Dai¹,

Chen²,

Xu³

2021

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Objective: To investigate the potential mechanism of Drynariae Rhizoma-Epimedii Folium in the treatment of osteoarthritis (OA) based on network pharmacology. Methods: The potential active constituents and targets of Drynariae Rhizoma-Epimedii Folium were screened through the traditional Chinese medicine (TCM) systems pharmacology database and analysis platform (TCMSP). Genecards database is used to find relevant targets of OA. The targets of "Drynariae Rhizoma-Epimedii Folium" were mapped to the targets of OA, and used Cytoscape software to build a "drug-ingredient-target-di-sease" regulatory network and protein protein interaction (PPI) network. R software was used to analyze the Gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment of traditional Chinese medicine-disease targets. Results: Thirty-four effective ingredients and 130 traditional Chinese medicine-disease targets were screened out for the treatment of OA. The GO functions of traditional Chinese medicine-disease targets mainly included cytokine activity, cytokine receptor binding, nuclear receptor activity, transcription factor activity, proximal promoter DNA-binding transcription activator activity, DNA-binding transcription activator activity, phosphatase binding and so on. KEGG pathways involved in traditional Chinese medicine-disease targets mainly included TLR4 signaling pathway, TNF signaling pathway, IL-17 signaling pathway, MAPK signaling pathway, PI3K/AKT signaling pathway, apoptotic signaling pathway and so on. Conclusion: Network pharmacology may predict the multiple targets and multiple signaling pathways in Drynariae Rhizoma-Epimedii Folium treatment for OA, providing new ideas for future research.

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Fisetin activates Hippo pathway and JNK/ERK/AP‐1 signaling to inhibit proliferation and induce apoptosis of human osteosarcoma cells via ZAK overexpression

Cited by 29 publications

References 28 publications

<p>Fisetin Modulates Human Oral Squamous Cell Carcinoma Proliferation by Blocking PAK4 Signaling Pathways</p>

<p>Fisetin Modulates Human Oral Squamous Cell Carcinoma Proliferation by Blocking PAK4 Signaling Pathways</p>

Fisetin Inhibits Osteogenic Differentiation of Mesenchymal Stem Cells via the Inhibition of YAP

Network Pharmacological Mechanism Research of Herba Drynariae Rhizoma-Epimedii Folium in Treating Osteoarthritis

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