title: Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells.
abstract: BACKGROUND
  Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women associated with an increased risk of endometrial hyperplasia. We sought to study the effects of metformin treatment (widely used in the management of PCOS women) on human endometrial adenocarcinoma cells.
  
  
  OBJECTIVE
  To study the effects of metformin treatment on in vitro invasion and metastasis in human endometrial adenocarcinoma cells. Also, given the link between inflammation with endometrial cancer invasion and metastasis, we explored the roles of nuclear factor-κB (NF-κB), matrix metalloproteinases (MMPs) as well as v-akt murine thymoma viral oncogene homolog 1 (Akt) and extracellular signal-regulated kinases (Erk(1/2)) signaling pathways.
  
  
  METHODS
  Sera were obtained from PCOS and control subjects. In vitro invasion were assessed in human endometrial cells (ECC-1 cells) by wound-healing motility and migration assays. NF-κB was studied by stably transfecting ECC-1 cells with a cis-reporter plasmid containing luciferase reporter gene linked to five repeats of NF-κB binding sites. The gelatinolytic activities of secreted MMP-2/9 in conditioned media were measured by gelatin zymography. Akt and Erk(1/2) phosphorylation were assessed by Western blotting.
  
  
  RESULTS
  In vitro invasion in ECC-1 cells was significantly attenuated by sera from PCOS women after 6 months of metformin treatment (850 mg twice daily) compared to matched controls (P < 0.01). These effects appear to be associated with NF-κB, MMP-2/9, as well as Akt and Erk(1/2) pathways that are known to be important regulators of inflammation, tumor invasion and metastasis.
  
  
  CONCLUSIONS
  Metformin, potentially, may serve as adjuvant treatment in the management of patients with endometrial cancer.
authors.affiliation: Endocrinology and Metabolism Group, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom. B.K.Tan.1@warwick.ac.uk
authors.forename: Bee K
authors.initials: BK
authors.lastname: Tan
authors.forename: Raghu
authors.initials: R
authors.lastname: Adya
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Sant Cassia
authors.forename: Harpal S
authors.initials: HS
authors.lastname: Randeva
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D016889:Endometrial Neoplasms / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000502:physiology; D008687:Metformin / Q000494:pharmacology*; D016328:NF-kappa B / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D051058:Oncogene Protein v-akt / Q000502:physiology; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000502:physiology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D016328:NF-kappa B; D008687:Metformin; D000242:Cyclic AMP; D051058:Oncogene Protein v-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases