Inhibition of histamine receptor H3 suppresses the growth and metastasis of human non-small cell lung cancer cells via inhibiting PI3K/Akt/mTOR and MEK/ERK signaling pathways and blocking EMT

Zhao, Yanyan; Jia, Jun; Zhang, Jingjing; Xun, Yunhao; Xie, Shujun; Liang, Junying; Guo, Honggang; Zhu, Jun; Ma, Shenglin; Zhang, Shirong

doi:10.1038/s41401-020-00548-6

Cited by 26 publications

(18 citation statements)

References 39 publications

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“…In carcinoma cells H 3 R -mediated activation of protein kinase C α inhibited the growth of cholangiocarcinoma and hepatocellular carcinoma cells ( Francis et al, 2009 ; Yu et al, 2019 ). The finding that blocking the H 3 R by CPX in the presence of TNFα enhanced cell differentiation, is also in line with studies on cancer cells reporting that inhibition of histamine receptor H 3 suppresses the growth and metastasis in human non-small cell lung cancer cells ( Zhao et al, 2020 ) thus potentially promoting differentiation. Moreover, the enhanced inflammation induced by CPX + TNFα could also direct cells into apoptosis resulting in the release of ATP, which further activates the NLRP3 inflammasome ( Jo et al, 2016 ).…”

Section: Discussionsupporting

confidence: 86%

Histamine H3 Receptor Signaling Regulates the NLRP3 Inflammasome Activation in C2C12 Myocyte During Myogenic Differentiation

Chen

Jin

et al. 2021

Front. Pharmacol.

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NLRP3 inflammasome has been implicated in impaired post-injury muscle healing and in muscle atrophy. Histamine receptors play an important role in inflammation, but the role of histamine H3 receptor (H3R) in myocyte regeneration and in the regulation of NLRP3 inflammasome is not known. We studied the effects of H3R signaling on C2C12 myocyte viability, apoptosis, and tumor necrosis factor alpha (TNFα)-induced NLRP3 inflammasome activation during striated myogenic differentiation at three time points (days 0, 3, and 6). Expression of Nlrp3, interleukin-1β (IL-1β), and myogenesis markers were determined. TNFα reduced overall viability of C2C12 cells, and exposure to TNFα induced apoptosis of cells at D6. Activation of H3R had no effect on viability or apoptosis, whereas inhibition of H3R increased TNFα-induced apoptosis. Stimulation of C2C12 cells with TNFα increased Nlrp3 mRNA expression at D3 and D6. Moreover, TNFα reduced the expression of myogenesis markers MyoD1, Myogenin, and Myosin-2 at D3 and D6. H3R attenuated TNFα-induced expression of Nlrp3 and further inhibited the myogenesis marker expression; while H3R -blockage enhanced the proinflammatory effects of TNFα and increased the myogenesis marker expression. TNFα-induced secretion of mature IL-1β was dependent on the activation of the NLRP3 inflammasome, as shown by the reduced secretion of mature IL-1β upon treatment of the cells with the small molecule inhibitor of the NLRP3 inflammasome (MCC950). The activation of H3R reduced TNFα-induced IL-1β secretion, while the H3R blockage had an opposite effect. In conclusion, the modulation of H3R activity regulates the effects of TNFα on C2C12 myocyte differentiation and TNFα-induced activation of NLRP3 inflammasome. Thus, H3R signaling may represent a novel target for limiting postinjury muscle inflammation and muscle atrophy.

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Section: Discussionsupporting

confidence: 86%

Histamine H3 Receptor Signaling Regulates the NLRP3 Inflammasome Activation in C2C12 Myocyte During Myogenic Differentiation

Chen

Jin

et al. 2021

Front. Pharmacol.

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“…Based on the observation that high expression levels of H3R were correlated with poor OS in NSCLC patients, they employed ciproxifan (an H3R antagonist) to test its antitumor activities and found that ciproxifan exerted moderate and concentration-dependent inhibition of cell proliferation and induced apoptosis in NSCLC cells. Their migration and invasion were also inhibited by ciproxifan, which was mediated by EMT inhibition via reducing phosphorylation of the PI3K/Akt/mTOR and MEK/ERK pathways [184]. These results were also confirmed in an in vivo study using nude mice bearing H1975 or A549 cell xenografts.…”

Section: Histamine H3 Receptorsupporting

confidence: 56%

“…The involvement of H3R in the growth and metastasis of NSCLC was recently revealed by Zhao et al [184]. Based on the observation that high expression levels of H3R were correlated with poor OS in NSCLC patients, they employed ciproxifan (an H3R antagonist) to test its antitumor activities and found that ciproxifan exerted moderate and concentration-dependent inhibition of cell proliferation and induced apoptosis in NSCLC cells.…”

Section: Histamine H3 Receptormentioning

confidence: 99%

“…Evidence indicating a potential relationship between H3R and cancer is scarce, and key questions remain elusive. Recent studies, however, have demonstrated that H3R expression is upregulated in several types of cancer, including GC, HCC, BC, lung cancer, and MM cancer cells [12,183,184], suggesting that H3R appears to diversify their signaling effects in these cell lines. After the publication of these studies, more attention has been paid to in vitro and in vivo studies to elaborate on the involvement of H3R in cancer.…”

Section: Histamine H3 Receptormentioning

confidence: 99%

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Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets

Nguyen

Cho

2021

Biomolecules

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High levels of histamine and histamine receptors (HRs), including H1R~H4R, are found in many different types of tumor cells and cells in the tumor microenvironment, suggesting their involvement in tumor progression. This review summarizes the latest evidence demonstrating the pathophysiological roles of histamine and its cognate receptors in cancer biology. We also discuss the novel therapeutic approaches of selective HR ligands and their potential prognostic values in cancer treatment. Briefly, histamine is highly implicated in cancer development, growth, and metastasis through interactions with distinct HRs. It also regulates the infiltration of immune cells into the tumor sites, exerting an immunomodulatory function. Moreover, the effects of various HR ligands, including H1R antagonists, H2R antagonists, and H4R agonists, on tumor progression in many different cancer types are described. Interestingly, the expression levels of HR subtypes may serve as prognostic biomarkers in several cancers. Taken together, HRs are promising targets for cancer treatment, and HR ligands may offer novel therapeutic potential, alone or in combination with conventional therapy. However, due to the complexity of the pathophysiological roles of histamine and HRs in cancer biology, further studies are warranted before HR ligands can be introduced into clinical settings.

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“…COL23A1 has an important paralog of this gene is COL5A1.The KEGG results showed that COL5A1 is related to the ECM-receptor interaction, protein digestion and absorption, focal adhesion, amoebiasis, and phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt) signaling pathways. These cellular pathways indicate that the body is in a state of accelerated metabolism, and the PI3K-Akt signaling pathway is a typical tumor metabolism pathway [26,27]. In recent years, several studies have shown that COL23A1 is closely related to renal cell carcinoma, head and neck cancer, and so on [28,29].…”

Section: Discussionmentioning

confidence: 99%

Identification of potential key genes in anaplastic thyroid cancer using bioinformatics analysis

Xiong

Wei

et al. 2021

Preprint

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Background Anaplastic thyroid cancer (ATC) has a high degree of malignancy and a poor prognosis. Its incidence accounts for approximately 10–15% of all thyroid cancers. The purpose of this study was to determine the differentially expressed genes (DEGs) of ATC through biometric analysis technology, clarify the potential interactions between them, and screen genes related to the prognosis of ATC. Methods The GSE29265, GSE65144, GSE33630, and GSE85457 expression profiles downloaded from the Gene Expression Omnibus database (GEO) contained a total of 117 tissue samples (81 normal thyroid tissue samples and 36 ATC samples). The four datasets were integrated and analyzed by the limma packages to obtain DEGs. With these DEGs, we performed gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway analyses using the Database for Annotation, Visualization and Integrated Discovery, protein-protein interaction (PPI) analysis using Cytoscape, and survival analysis using the Kaplan-Meier (KM) plotter. Results. After R integration analysis of the four datasets, 764 DEGs were obtained, i.e., 314 upregulated and 450 downregulated genes. Among the hub DEGs obtained in the PPI network, the expression levels of thymidylate synthase (TYMS), fibronectin 1, chordin-like 1, syndecan 2, integrin alpha 2, collagen type I alpha 1 chain, collagen type IX alpha 3 chain (COL9A3), and collagen type XXIII alpha 1 chain (COL23A1) were associated with ATC prognosis. These results showed that the overall survival and recurrence-free survival of TYMS, COL9A3, and COL23A1 were statistically significant in our KM plotter survival analysis; thus, these DEGs may be used as potential biomarkers of ATC. Conclusion This study identified several potential target genes and pathways that may affect the development of ATC. These findings provide new insights for the detection of novel diagnostic and therapeutic biomarkers for ATC.

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Inhibition of histamine receptor H3 suppresses the growth and metastasis of human non-small cell lung cancer cells via inhibiting PI3K/Akt/mTOR and MEK/ERK signaling pathways and blocking EMT

Cited by 26 publications

References 39 publications

Histamine H3 Receptor Signaling Regulates the NLRP3 Inflammasome Activation in C2C12 Myocyte During Myogenic Differentiation

Histamine H3 Receptor Signaling Regulates the NLRP3 Inflammasome Activation in C2C12 Myocyte During Myogenic Differentiation

Pathophysiological Roles of Histamine Receptors in Cancer Progression: Implications and Perspectives as Potential Molecular Targets

Identification of potential key genes in anaplastic thyroid cancer using bioinformatics analysis

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