基于mTOR信号通路研究桦木酸对肿瘤相关巨噬细胞复极化影响以及对非小细胞肺癌的抗肿瘤作用  

Betulinic acid inhibits non-small cell lung cancer by repolarizing tumor-associated macrophages via mTOR signaling pathway

作　　者：曾安琪 陈雪 戴瑛[1] 赵军宁[1] ZENG An-qi;CHEN Xue;DAI Ying;ZHAO Jun-ning(Key Laboratory of Biological Evaluation of Quality of Traditional Chinese Medicine,National Administration of Traditional Chinese Medicine,Sichuan Key Laboratory of Translational Chinese Medicine,Sichuan Provincial Engineering Research Center of Formation Principle and Quality Evaluation of Genuine Medicinal Materials,Sichuan Engineering Technology Research Center of Genuine Medicinal Materials,Sichuan Institute for Translational Chinese Medicine,Sichuan Academy of Chinese Medicine Sciences,Chengdu 610041,China)

机构地区：[1]四川省中医药科学院,四川省中医药转化医学中心,国家中医药管理局中药质量生物评价重点研究室,中医药转化医学四川省重点实验室,四川省道地药材形成原理与品质评价工程研究中心,四川省道地药材系统开发工程技术研究中心,四川成都610041

出　　处：《中国中药杂志》2024年第9期2376-2384,共9页China Journal of Chinese Materia Medica

基　　金：四川省省级科研院所基本科研业务项目[2022JDKY0036(A-2022N-Z-1),2023JDKY0038(A-2023N-Z-4)]。

摘　　要：非小细胞肺癌(NSCLC)中哺乳动物雷帕霉素靶蛋白(mTOR)信号通路的异常激活与远端转移、耐药、肿瘤免疫逃逸和低生存率密切相关。该研究报道了桦木酸(BA)是一种有效的mTOR信号通路抑制剂,在体外和体内对NSCLC细胞表现出有效的抗肿瘤活性。CCK-8和集落形成结果表明,BA可显著抑制H1299、A549和LLC细胞的活力和克隆生成能力。BA处理可诱导线粒体介导的H1299和LLC细胞凋亡;通过下调MMP2的表达和损害上皮-间质转化,明显抑制H1299和LLC细胞的移动性和侵袭能力。研究结果表明,BA处理可抑制mTOR信号通路,从而抑制M2表型(CD206阳性)巨噬细胞的某些方面。随后,为了评估桦木酸在LLC体内的抗肿瘤作用,利用LLC细胞建立小鼠异种移植肿瘤模型。结果表明,BA能显著延缓肿瘤的生长,抑制肿瘤细胞的增殖。更重要的是,给药BA后,肿瘤组织中M1/M2肿瘤相关巨噬细胞的比例显著升高,表明抗肿瘤免疫能力增强。综上所述,该研究结果表明,BA可通过mTOR信号通路使肿瘤相关巨噬细胞复极化,从而对NSCLC细胞具有抗肿瘤作用。The abnormal activation of the mammalian target of rapamycin(mTOR)signaling pathway in non-small cell lung cancer(NSCLC)is closely associated with distant metastasis,drug resistance,tumor immune escape,and low overall survival.The present study reported that betulinic acid(BA),a potent inhibitor of mTOR signaling pathway,exhibited an inhibitory activity against NSCLC in vitro and in vivo.CCK-8 and colony formation results demonstrated that BA significantly inhibited the viability and clonogenic ability of H1299,A549,and LLC cells.Additionally,the treatment with BA induced mitochondrion-mediated apoptosis of H1299 and LLC cells.Furthermore,BA inhibited the mobility and invasion of H1299 and LLC cells by down-regulating the expression level of matrix metalloproteinase 2(MMP2)and impairing epithelial-mesenchymal transition.The results demonstrated that the inhibition of mTOR signaling pathway by BA decreased the proportion of M2 phenotype(CD206 positive)cells in total macrophages.Furthermore,a mouse model of subcutaneous tumor was established with LLC cells to evaluate the anti-tumor efficiency of BA in vivo.The results revealed that the administration of BA dramatically retarded the tumor growth and inhibited the proliferation of tumor cells.More importantly,BA increased the ratio of M1/M2 macrophages in the tumor tissue,which implied the enhancement of anti-tumor immunity.In conclusion,BA demonstrated the inhibitory effect on NSCLC by repolarizing tumor-associated macrophages via the mTOR signaling pathway.

关 键 词：桦木酸 非小细胞肺癌 MTOR信号通路 肿瘤相关巨噬细胞 

分 类 号：R285[医药卫生—中药学]