title: Metformin Induced AMPK Activation, G0/G1 Phase Cell Cycle Arrest and the Inhibition of Growth of Esophageal Squamous Cell Carcinomas In Vitro and In Vivo.
abstract: Esophageal squamous cell carcinomas (ESCC) have become a severe threat to health and the current treatments for ESCC are frequently not effective. Recent epidemiological studies suggest that the anti-hyperglycemic agent metformin may reduce the risk of developing cancer, including ESCC, among diabetic patients. However, the antitumor effects of metformin on ESCC and the mechanisms underlying its cell cycle regulation remain elusive. The findings reported herein show that the anti-proliferative action of metformin on ESCC cell lines is partially mediated by AMPK. Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1. In vivo experiments further showed that metformin inhibited tumor growth in a ESCC xenograft model. Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo. In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model. AMPK, p53, p21CIP1, p27KIP1 and cyclinD1 are involved in the inhibition of tumor growth that is induced by metformin and cell cycle arrest in ESCC. These findings indicate that metformin has the potential for use in the treatment of ESCC.
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.
authors.forename: Xianbin
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Internal Medicine, Chancheng District Central Hospital, Foshan, Guangdong 528031, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.
authors.forename: Qinjia
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.
authors.forename: Xubin
authors.initials: X
authors.lastname: Jing
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008819:Mice, Nude; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007004:Hypoglycemic Agents; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008687:Metformin; D055372:AMP-Activated Protein Kinases