OncoTargets and Therapy (May 2020)
Metformin Promotes Beclin1-Dependent Autophagy to Inhibit the Progression of Gastric Cancer
Abstract
Su Liu,1 Chao Yue,1 Huanqiu Chen,1 Yun Chen,2 Gang Li1 1Department of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, People’s Republic of China; 2Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, Jiangsu 211166, People’s Republic of ChinaCorrespondence: Gang LiDepartment of General Surgery, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, People’s Republic of ChinaTel +862583284745Email [email protected] ChenDepartment of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, Jiangsu 211166, People’s Republic of ChinaEmail [email protected]: Metformin is the first-line blood sugar control drug for type 2 diabetes, but recent epidemiological studies have shown that it inhibits the growth of a variety of tumours. However, few studies have examined metformin effects on gastric cancer (GC), and the anticancer mechanism has not been fully elucidated.Materials and Methods: We examined the inhibitory effect of metformin on GC cells by cell proliferation, migration and invasion assay. Transmission electron microscopy, confocal microscopy and Western blotting confirmed that metformin enhanced beclin1-dependent autophagy in gastric cancer cells. TCGA database and tissue chip analysis confirmed the differential expression of beclin1 in GC and adjacent tissues. Relevant functional tests verified the role of beclin1 as a tumour suppressor gene in GC. Western blotting, cell proliferation, cell migration and invasion were used to verify that metformin enhances autophagy in GC cells through the AMPK-mTOR signalling pathway. Xenograft tumour models were constructed to explore the inhibitory effect of metformin and the role of beclin1 as a suppressor on GC in vivo.Results: In this study, we observed that metformin inhibits proliferation, migration and invasion of GC cells. Metformin could also promote beclin1-dependent autophagy in GC cells. We further discovered that beclin1 expression was downregulated in GC and that its low expression was associated with poor prognosis. Beclin1 acts as a tumour suppressor that inhibits the malignant phenotypes of GC cells in vitro and in vivo. Furthermore, we verified that metformin can upregulate beclin1-mediated autophagy to inhibit GC cells through the AMPK-mTOR signalling pathway.Conclusion: In summary, the results revealed the role of autophagy in metformin inhibition of gastric cancer and suggest that beclin1 may be a potential target for gastric cancer therapy.Keywords: metformin, gastric cancer, GC, autophagy, beclin1, AMPK-mTOR signalling pathway
