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

Yan-yan Zhao1, Jing Jia2, Jing-jing Zhang1, Yan-ping Xun1, Shu-jun Xie1, Jia-feng Liang1, Hong-gang Guo2, Jia-zhen Zhu3, Sheng-lin Ma1,4, Shi-rong Zhang1
1 Department of Translation Medicine Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
2 Center for Molecular Medicine, Zhejiang Academy of Medical Sciences, Hangzhou 310006, China
3 College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou 310006, China
4 Department of Oncology, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
Correspondence to: Sheng-lin Ma:, Shi-rong Zhang:,
DOI: 10.1038/s41401-020-00548-6
Received: 12 December 2019
Accepted: 24 September 2020
Advance online: 6 November 2020


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.
Keywords: non-small cell lung cancer; histamine receptor h3; apoptosis; cell migration and invasion; epithelia-mesenchymal transition; metastasis; ciproxifan; RAMH

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