Metformin suppresses the esophageal carcinogenesis in rats treated with NMBzA through inhibiting AMPK/mTOR signaling pathway
Metformin suppresses the esophageal carcinogenesis in rats treated with NMBzA through inhibiting AMPK/mTOR signaling pathway
复制标题
二甲双胍通过抑制 AMPK/mTOR 信号通路抑制 NMBzA 大鼠食管癌发生
DOI：
10.1093/carcin/bgy160
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发表时间：
2019-05-01
期刊：
影响因子：
4.7
通讯作者：
Lu, Shih-Hsin
中科院分区：
文献类型：
--
作者：
Fan, Hongjun;Yu, Xiying;Lu, Shih-Hsin
二甲双胍对NMBzA诱导的ESCC有化学预防作用。二甲双胍在体内和体外诱导的NMBzA诱导的大鼠癌前病变和肿瘤以及人ESCC细胞中激活AMPK，减弱下游信号分子如mTOR、p-p70S6K和cyclin D1。摘要二甲双胍是一种广泛应用于2型糖尿病治疗的降糖药。近年来，流行病学研究表明，二甲双胍对食管鳞状细胞癌（ESCC）等肿瘤有抗癌作用。然而，二甲双胍对ESCC的影响及其潜在机制尚不清楚。本研究采用食道专用致癌物n -亚硝基-n -甲基苄胺（NMBzA）建立大鼠ESCC模型，诱导并促进大鼠ESCC的癌变进程。我们在该模型中研究二甲双胍对ESCC癌变的影响。我们的研究结果显示，二甲双胍显著降低了NMBzA处理大鼠ESCC的发生率和癌前病变，抑制了食管上皮细胞的增殖并促进了细胞凋亡。此外，二甲双胍还能增加体外培养的人ESCC细胞的凋亡，抑制细胞迁移、集落形成和肿瘤球形成。免疫组织化学和western blotting结果显示，在不干扰NMBzA代谢的情况下，二甲双胍通过降低诱导型一氧化氮合酶（iNOS）、环氧合酶-2 （COX-2）和白细胞介素-6 （IL-6）的表达抑制了食管炎症。二甲双胍处理导致amp活化蛋白激酶（AMPK）的激活，并减弱下游分子如p-mTOR， p-p70S6K和cyclin D1在体内和体外的表达。综上所述，我们的研究表明，二甲双胍通过抑制rapamycin （mTOR）信号通路的AMPK/哺乳动物靶点来抑制ESCC的癌变，从而对ESCC的癌变产生化学预防作用。
Metformin showed chemopreventive effect on the carcinogenesis of ESCC induced by NMBzA in rats. Treatment with metformin led to activation of AMPK and attenuated the downstream signaling molecules such as mTOR, p-p70S6K and cyclin D1 in both rat precancerous lesions and tumors induced by NMBzA in vivo and human ESCC cells in vitro.Abstract Metformin is a widely used antidiabetic drug for the management of type 2 diabetes mellitus. Recently, epidemiological studies demonstrate that metformin has anticancer effects on esophageal squamous cell carcinoma (ESCC) and other cancers. However, the effects and potential mechanisms of metformin on ESCC remain elusive. In this study, we used N-nitroso-N-methylbenzylamine (NMBzA), a special carcinogen for esophagi, to develop a rat ESCC model, in which the carcinogenesis progression of ESCC in rat was induced and promoted. We investigated the effects of metformin on carcinogenesis of ESCC in this model. Our results revealed that metformin significantly decreased the incidence and precancerous lesions of ESCC and inhibited proliferation and promoted apoptosis of esophageal epithelial cells in rat treated with NMBzA. Moreover, metformin also increased apoptosis and inhibited migration, colony formation and tumor sphere formation of human ESCC cells in vitro. Immunohistochemistry and western blotting showed that without interfering the metabolism of NMBzA, metformin inhibited the inflammation of esophagi via reducing the expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6). Treatment of metformin led to activation of AMP-activated protein kinase (AMPK) and attenuated signaling of the downstream molecules such as p-mTOR, p-p70S6K and cyclin D1 expression both in vivo and in vitro. Taken together, our study demonstrated that metformin suppressed the carcinogenesis of ESCC through inhibiting AMPK/mammalian target of the rapamycin (mTOR) signaling pathway, resulting in its chemopreventive effects on the carcinogenesis of ESCC.