title: The anti-diabetic drug metformin inhibits pancreatic cancer cell proliferation in vitro and in vivo: Study of the microRNAs associated with the antitumor effect of metformin.
abstract: Recent studies suggest that metformin, which is a commonly used oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, yet the detailed mechanisms by which metformin affects various types of cancers, including pancreatic cancer, remain unknown. The aim of the present study was to evaluate the effects of metformin on human pancreatic cancer cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin. We used the human pancreatic cancer cell lines Panc1, PK1 and PK9 to study the effects of metformin on human pancreatic cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 5 weeks, and the expression of cell cycle-related proteins was determined. In addition, we used miRNA microarray tips to explore the differences in the levels of miRNAs in Panc1 cells and xenograft tumors treated with metformin or without. Metformin inhibited the proliferation of Panc1, PK1 and PK9 cells in vitro. This inhibition was accompanied by a strong decrease in G1 cyclins (particularly in cyclin D1) and retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor (EGFR), particularly the phosphorylation of EGFR at Tyr845, and insulin-like growth factor 1 receptor (IGF-1R) in vitro and in vivo. miRNA expression was markedly altered by the treatment with metformin in vitro and in vivo. Our results revealed that metformin inhibits human pancreatic cancer cell proliferation and tumor growth, possibly by suppressing the cell cycle-related molecules via alteration of miRNAs.
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa Prefecture 761-0793, Japan.
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Kato
authors.affiliation: Life Science Research Center, Kagawa University, Kita-gun, Kagawa Prefecture 761-0793, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Iwama
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa Prefecture 761-0793, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa Prefecture 761-0793, Japan.
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa Prefecture 761-0793, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Fujihara
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa Prefecture 761-0793, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujimori
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa Prefecture 761-0793, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kamada
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa Prefecture 761-0793, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kobara
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa Prefecture 761-0793, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: C530104:CCND1 protein, human; D007004:Hypoglycemic Agents; D035683:MicroRNAs; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D008687:Metformin; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1