title: Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling.
abstract: OBJECTIVE
  To further elucidate the anticancer mechanisms of metformin against pancreatic cancer, we evaluated the inhibitory effects of metformin on pancreatic tumorigenesis in a genetically engineered mouse model and investigated its possible anti-inflammatory and antiangiogenesis effects.
  
  
  METHODS
  Six-week-old LSL-Kras;Trp53 mice (10 per group) were administered once daily intraperitoneally with saline (control) for 1 week or metformin (125 mg/kg) for 1 week (Met_1wk) or 3 weeks (Met_3wk) before tumor initiation. All mice continued with their respective injections for 6 weeks after tumor initiation. Molecular changes were evaluated through quantitative polymerase chain reaction, immunohistochemistry, and Western blotting.
  
  
  RESULTS
  At euthanasia, pancreatic tumor volume in the Met_1wk (median, 181.8 mm) and Met_3wk (median, 137.9 mm) groups was significantly lower than those in the control group (median, 481.1 mm; P = 0.001 and 0.0009, respectively). No significant difference was observed between the Met_1wk and Met_3wk groups (P = 0.51). These results were further confirmed using tumor weight and tumor burden measurements. Furthermore, metformin treatment decreased the phosphorylation of nuclear factor κB and signal transducer and activator of transcription 3 as well as the expression of specificity protein 1 transcription factor and several nuclear factor κB-regulated genes.
  
  
  CONCLUSIONS
  Metformin may inhibit pancreatic tumorigenesis by modulating multiple molecular targets in inflammatory pathways.
authors: From the *Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN; †Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick; ‡Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, Piscataway, NJ; and §Department of Biochemistry and Molecular Biology, ∥Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, and ¶Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.
authors: Xiang-Lin
authors: XL
authors: Tan
authors: Kalyan K
authors: KK
authors: Bhattacharyya
authors: Shamit K
authors: SK
authors: Dutta
authors: William R
authors: WR
authors: Bamlet
authors: Kari G
authors: KG
authors: Rabe
authors: Enfeng
authors: E
authors: Wang
authors: Thomas C
authors: TC
authors: Smyrk
authors: Ann L
authors: AL
authors: Oberg
authors: Gloria M
authors: GM
authors: Petersen
authors: Debabrata
authors: D
authors: Mukhopadhyay
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015153:Blotting, Western; D004334:Drug Administration Schedule; D005260:Female; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D008687:Metformin