Metformin suppresses the esophageal carcinogenesis in rats treated with NMBzA through inhibiting AMPK/mTOR signaling pathway

Author:

Fan Hongjun12ORCID,Yu Xiying12,Zou Zhigeng12,Zheng Wei12,Deng Xin12,Guo Liping12,Jiang Wei1,Zhan Qimin3,Lu Shih-Hsin124

Affiliation:

1. Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology

2. Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital and Institute, Beijing, China

4. Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Abstract

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.

Funder

CAMS Innovation Fund for Medical Sciences

National Key Basic Research Program of China

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,General Medicine

Reference43 articles.

1. Global cancer statistics;Jemal;CA. Cancer J. Clin.,2011

2. Cancer statistics in China, 2015;Chen;CA. Cancer J. Clin.,2016

3. Population attributable risks of esophageal and gastric cancers;Engel;J. Natl. Cancer Inst.,2003

4. Alterations of oncogenes and tumor suppressor genes in esophageal cancer in China;Lu;Mutat. Res.,2000

5. [Mortality and survival analysis of esophageal cancer in China];Zhang;Zhonghua Zhong Liu Za Zhi,2016

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