title: High Glucose-Mediated STAT3 Activation in Endometrial Cancer Is Inhibited by Metformin: Therapeutic Implications for Endometrial Cancer.
abstract: OBJECTIVE
  STAT3 is over-expressed in endometrial cancer, and diabetes is a risk factor for the development of type 1 endometrial cancer. We therefore investigated whether glucose concentrations influence STAT3 expression in type 1 endometrial cancer, and whether such STAT3 expression might be inhibited by metformin.
  
  
  METHODS
  In Ishikawa (grade 1) endometrial cancer cells subjected to media with low, normal, or high concentrations of glucose, expression of STAT3 and its target proteins was evaluated by real-time quantitative PCR (qPCR). Ishikawa cells were treated with metformin and assessed with cell proliferation, survival, migration, and ubiquitin assays, as well as Western blot and qPCR. Expression of apoptosis proteins was evaluated with Western blot in Ishikawa cells transfected with a STAT3 overexpression plasmid and treated with metformin. A xenograft tumor model was used for studying the in vivo efficacy of metformin.
  
  
  RESULTS
  Expression of STAT3 and its target proteins was increased in Ishikawa cells cultured in high glucose media. In vitro, metformin inhibited cell proliferation, survival and migration but induced apoptosis. Metformin reduced expression levels of pSTAT3 ser727, total STAT3, and its associated cell survival and anti-apoptotic proteins. Additionally, metformin treatment was associated with increased degradation of pSTAT3 ser727. No change in apoptotic protein expression was noticed with STAT3 overexpression in Ishikawa cells. In vivo, metformin treatment led to a decrease in tumor weight as well as reductions of STAT3, pSTAT3 ser727, its target proteins.
  
  
  CONCLUSIONS
  These results suggest that STAT3 expression in type 1 endometrial cancer is stimulated by a high glucose environment and inhibited by metformin.
authors.affiliation: Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Wallbillich
authors.affiliation: Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Srirama
authors.initials: S
authors.lastname: Josyula
authors.affiliation: Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Uksha
authors.initials: U
authors.lastname: Saini
authors.affiliation: Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Zingarelli
authors.affiliation: Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Kalpana Deepa Priya
authors.initials: KD
authors.lastname: Dorayappan
authors.affiliation: Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Riley
authors.affiliation: Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Wanner
authors.affiliation: Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: David E
authors.initials: DE
authors.lastname: Cohn
authors.affiliation: Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Karuppaiyah
authors.initials: K
authors.lastname: Selvendiran
mesh_terms: D000818:Animals; D016889:Endometrial Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005260:Female; D005947:Glucose / Q000008:administration & dosage*; D064593:Heterografts; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D008687:Metformin; D005947:Glucose