Abstract
Recent evidence shows that the expression levels of histamine receptor H3 (Hrh3) are upregulated in several types of cancer. However, the role of Hrh3 in non-small cell lung cancer (NSCLC) has not been elucidated. In the present study, we showed that the expression levels of Hrh3 were significantly increased in NSCLC samples, and high levels of Hrh3 were associated with poor overall survival (OS) in NSCLC patients. In five human NSCLC cell lines tested, Hrh3 was significantly upregulated. In NSCLC cell lines H1975, H460, and A549, Hrh3 antagonist ciproxifan (CPX, 10–80 μM) exerted moderate and concentration-dependent inhibition on the cell growth and induced apoptosis, whereas its agonist RAMH (80 μM) reversed these effects. Furthermore, inhibition of Hrh3 by CPX or siRNA retarded the migration and invasion of NSCLC cells through inhibiting epithelial-mesenchymal transition (EMT) progression via reducing the phosphorylation of PI3K/Akt/mTOR and MEK/ERK signaling pathways. In nude mice bearing H1975 cell xenograft or A549 cell xenograft, administration of CPX (3 mg/kg every other day, intraperitoneal) significantly inhibited the tumor growth with increased E-cadherin and ZO-1 expression and decreased Fibronectin expression in tumor tissue. In conclusion, this study reveals that Hrh3 plays an important role in the growth and metastasis of NSCLC; it might be a potential therapeutic target against the lung cancer.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.
Dai L, Smith CD, Foroozesh M, Miele L, Qin Z. The sphingosine kinase 2 inhibitor ABC294640 displays anti-non-small cell lung cancer activities in vitro and in vivo. Int J Cancer. 2018;142:2153–62.
Torre LA, Siegel RL, Jemal A. Lung cancer statistics. Adv Exp Med Biol. 2016;893:1–19.
Lin JJ, Zhao TZ, Cai WK, Yang YX, Sun C, Zhang Z, et al. Inhibition of histamine receptor 3 suppresses glioblastoma tumor growth, invasion, and epithelial-to-mesenchymal transition. Oncotarget. 2015;6:17107–20.
Fang Z, Yao W, Xiong Y, Li J, Liu L, Shi L, et al. Attenuated expression of HRH4 in colorectal carcinomas: a potential influence on tumor growth and progression. BMC Cancer. 2011;11:1–11.
Cai WK, Hu J, Li T, Meng JR, Ma X, Yin SJ, et al. Activation of histamine H4 receptors decreases epithelial-to-mesenchymal transition progress by inhibiting transforming growth factor-beta1 signalling pathway in non-small cell lung cancer. Eur J Cancer. 2014;50:1195–206.
Meng F, Han Y, Staloch D, Francis T, Stokes A, Francis H. The H4 histamine receptor agonist, clobenpropit, suppresses human cholangiocarcinoma progression by disruption of epithelial mesenchymal transition and tumor metastasis. Hepatology. 2011;54:1718–28.
Davenas E, Rouleau A, Morisset S, Arrang JM. Autoregulation of McA-RH7777 hepatoma cell proliferation by histamine H3 receptors. J Pharmacol Exp Ther. 2008;326:406–13.
Zhang C, Xiong Y, Li J, Yang Y, Liu L, Wang W, et al. Deletion and down-regulation of HRH4 gene in gastric carcinomas: a potential correlation with tumor progression. PLoS One. 2012;7:e31207.
Tanaka S, Sakaguchi M, Yoneyama H, Usami Y, Harusawa S. Histamine H3 receptor antagonist OUP-186 attenuates the proliferation of cultured human breast cancer cell lines. Biochem Biophys Res Commun. 2016;480:479–85.
Hill SJ, Ganellin CR, Timmerman H, Schwartz JC, Shankley NP, Young JM, et al. International Union of Pharmacology. XIII. Classification of histamine receptors. Pharmacol Rev. 1997;49:253–78.
Lai X, Ye L, Liao Y, Jin L, Ma Q, Lu B, et al. Agonist-induced activation of histamine H3 receptor signals to extracellular signal-regulated kinases 1 and 2 through PKC-, PLD-, and EGFR-dependent mechanisms. J Neurochem. 2016;137:200–15.
Medina V, Croci M, Crescenti E, Mohamad N, Sanchez-Jimenez F, Massari N, et al. The role of histamine in human mammary carcinogenesis: H3 and H4 receptors as potential therapeutic targets for breast cancer treatment. Cancer Biol Ther. 2008;7:28–35.
Hough LB. Genomics meets histamine receptors: new subtypes, new receptors. Mol Pharmacol. 2001;59:415–9.
Haas HL, Sergeeva OA, Selbach O. Histamine in the nervous system. Physiol Rev. 2008;88:1183–241.
He GH, Lu J, Shi PP, Xia W, Yin SJ, Jin TB, et al. Polymorphisms of human histamine receptor H4 gene are associated with breast cancer in Chinese Han population. Gene. 2013;519:260–5.
He GH, Xu GL, Cai WK, Xia W. H3 or H4 histamine receptors: that which contributes to suppressing human cholangiocarcinoma progression still remains to be clarified. Hepatology. 2012;56:1182–3.
Wang T, Liu H, Pei L, Wang K, Song C, Wang P, et al. Screening of tumor-associated antigens based on Oncomine database and evaluation of diagnostic value of autoantibodies in lung cancer. Clin Immunol. 2019;210:108262.
Hou J, Aerts J, den Hamer B, van Ijcken W, den Bakker M, Riegman P, et al. Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PLoS One. 2010;5:e10312.
Morisset S, Rouleau A, Ligneau X, Gbahou F, Tardivel-Lacombe J, Stark H, et al. High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature. 2000;408:860–4.
Aquino-Miranda G, Escamilla-Sánchez J, González-Pantoja R, Bueno-Nava A, Arias-Montaño JA. Histamine H3 receptor activation inhibits dopamine synthesis but not release or uptake in rat nucleus accumbens. Neuropharmacology. 2016;106:91–101.
Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7:re8.
Nieto MA, Huang RY, Jackson RA, Thiery JP. Emt: 2016. Cell. 2016;166:21–45.
Singh M, Yelle N, Venugopal C, Singh SK. EMT: Mechanisms and therapeutic implications. Pharmacol Ther. 2018;182:80–94.
Zhang ZQ, Chen J, Huang WQ, Ning D, Liu QM, Wang C, et al. FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition via Akt signaling in hepatocellular carcinoma. Mol Oncol. 2019;13:792–810.
Misto A, Provensi G, Vozella V, Passani MB, Piomelli D. Mast cell-derived histamine regulates liver ketogenesis via oleoylethanolamide signaling. Cell Metab. 2019;29:91–102 e5.
Massari NA, Nicoud MB, Medina VA. Histamine receptors and cancer pharmacology: an update. Br J Pharmacol. 2020;177:516–38.
Yusen W, Xia W, Shengjun Y, Shaohui Z, Hongzhen Z. The expression and significance of tumor associated macrophages and CXCR4 in non-small cell lung cancer. J BUON. 2018;23:398–402.
Fan S, Zou Y, Wang Y, Fang F, Song W. An observational study of apatinib mesylate in treating advanced non-small cell lung cancer with unknown driving gene(s). J BUON. 2018;23:654–8.
Chen J, Hu XY. Inhibition of histamine receptor H3R suppresses prostate cancer growth, invasion and increases apoptosis via the AR pathway. Oncol Lett. 2018;16:4921–8.
Yu D, Zhao J, Wang Y, Hu J, Zhao Q, Li J, et al. Upregulated histamine receptor H3 promotes tumor growth and metastasis in hepatocellular carcinoma. Oncol Rep. 2019;41:3347–54.
Francis H, Onori P, Gaudio E, Franchitto A, DeMorrow S, Venter J, et al. H3 histamine receptor-mediated activation of protein kinase Calpha inhibits the growth of cholangiocarcinoma in vitro and in vivo. Mol Cancer Res. 2009;7:1704–13.
Hegyesi H, Horvath B, Pallinger E, Pos Z, Molnar V, Falus A. Histamine elevates the expression of Ets-1, a protooncogen in human melanoma cell lines through H2 receptor. FEBS Lett. 2005;579:2475–9.
Boer K, Helinger E, Helinger A, Pocza P, Pos Z, Demeter P, et al. Decreased expression of histamine H1 and H4 receptors suggests disturbance of local regulation in human colorectal tumours by histamine. Eur J Cell Biol. 2008;87:227–36.
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15:178–96.
Zavadil J, Bottinger EP. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene. 2005;24:5764–74.
Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Abbruzzese JL, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.
Paik WH, Ryu JK, Jeong K-S, Park JM, Song BJ, Lee SH, et al. Clobenpropit enhances anti-tumor effect of gemcitabine in pancreatic cancer. World J Gastroenterol. 2014;20:8545–57.
Li H, Yang L, Fu H, Yan J, Wang Y, Guo H, et al. Association between Galphai2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis. Nat Commun. 2013;4:1706.
Caggia S, Chunduri H, Millena AC, Perkins JN, Venugopal SV, Vo BT, et al. Novel role of Gialpha2 in cell migration: downstream of PI3-kinase-AKT and Rac1 in prostate cancer cells. J Cell Physiol. 2018;234:802–15.
Bongers G, Bakker RA, Leurs R. Molecular aspects of the histamine H3 receptor. Biochem Pharmacol. 2007;73:1195–204.
Ono H, Basson MD, Ito H. PTK6 promotes cancer migration and invasion in pancreatic cancer cells dependent on ERK signaling. PLoS One. 2014;9:e96060.
Acknowledgements
This study was supported by grants from the National Natural Science Foundation (81602555, 81803042), Natural Science Foundation of Zhejiang Province (LQ17H160003, LQ19H280004), Medical and Health Technology project of Zhejiang Province (2018KY580), the Traditional Chinese Medicine Science and Technology Plan of Zhejiang Province (2018ZQ012, 2018ZQ013), Social Development Application Project of Hangzhou (20180533B41). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Contributions
YYZ, SRZ, and SLM designed the experiments; YYZ, SRZ, and SLM were involved in project administration; YYZ and SRZ wrote and edited the manuscript; YYZ, JJ, JJZ, YPX, SJX, JFL, HGG, and JZZ performed experiments and analyzed the data.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Zhao, Yy., Jia, J., Zhang, Jj. et al. 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. Acta Pharmacol Sin 42, 1288–1297 (2021). https://doi.org/10.1038/s41401-020-00548-6
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41401-020-00548-6
Keywords
This article is cited by
-
ESPN activates ZEB1-mediated EMT through the PI3K/AKT/mTOR axis to promote osteosarcoma metastasis
Journal of Translational Medicine (2025)
-
G-protein coupled receptor 183 (GPR183) inhibits visceral metastasis of non-small cell lung cancer
Clinical & Experimental Metastasis (2025)
-
Mechanisms of Bone Morphogenetic Protein 2 in Respiratory Diseases
Current Allergy and Asthma Reports (2025)
-
PI3K/AKT pathway as a pivotal regulator of epithelial-mesenchymal transition in lung tumor cells
Cancer Cell International (2024)
-
ITGB4 is a prognostic biomarker and correlated with lung adenocarcinoma brain metastasis
Clinical and Translational Oncology (2024)
