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  

作　　者：Yan-yan Zhao Jing Jia Jing-jing Zhang Yan-ping Xun Shu-jun Xie Jia-feng Liang Hong-gang Guo Jia-zhen Zhu Sheng-lin Ma Shi-rong Zhang 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2021年第8期1288-1297,共10页中国药理学报（英文版）

基　　金：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).

摘　　要：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,10-80μM)exerted moderate and concentration-dependent inhibition on the cell growth and induced apoptosis,whereas its agonist RAMH(80μM)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.

关 键 词：non-small cell lung cancer histamine receptor h3 apoptosis cell migration and invasion epithelia-mesenchymal transition METASTASIS ciproxifan RAMH 

分 类 号：R734.2[医药卫生—肿瘤]