title: The anti-diabetic drug metformin inhibits vascular endothelial growth factor expression via the mammalian target of rapamycin complex 1/hypoxia-inducible factor-1α signaling pathway in ELT-3 cells.
abstract: The aim of this study was to elucidate whether metformin can regulate the expression of vascular endothelial growth factor (VEGF) in rat-derived uterine leiomyoma cells (ELT-3 cells). In vitro studies were conducted using ELT-3 cells. Under normoxic conditions, metformin suppressed VEGF protein levels in the supernatant and cells in a dose-dependent manner. In hypoxia-mimicking conditions, VEGF and hypoxia-inducible factor-1α (HIF-1α) proteins were both highly expressed and were suppressed by the metformin treatment. Metformin did not affect HIF-1α mRNA levels, which indicated that its effects occurred at the post-translational level. Metformin inhibited mammalian target of rapamycin complex 1 (mTORC1) activity by phosphorylating the mTORC1 component raptor. This study revealed the anti-angiogenic activity of metformin in ELT-3 cells by suppressing the expression of VEGF via the mTORC1/HIF-1α pathway. These results indicate that metformin may represent an effective alternative in the future treatment of uterine leiomyomas.
authors.affiliation: Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Aobaku, Seiryo-cho, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Tadakawa
authors.affiliation: Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Aobaku, Seiryo-cho, Sendai, Miyagi, 980-8574, Japan; Division of Women's Health, Research Institute of Traditional Asian Medicine, Kinki University School of Medicine, 377-2 Oono-Higashi, Osaka-Sayama, Osaka, 589-8511, Japan. Electronic address: take@med.kindai.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takeda
authors.affiliation: Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Aobaku, Seiryo-cho, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Aobaku, Seiryo-cho, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tsuiji
authors.affiliation: Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, 1-1 Aobaku, Seiryo-cho, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Yaegashi
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007889:Leiomyoma / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D020533:Angiogenesis Inhibitors; C497444:Hif1a protein, rat; D007004:Hypoglycemic Agents; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D008687:Metformin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Angiogenesis; HIF-1α; Metformin; Uterine leiomyoma; VEGF; mTOR