Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling

Xiang Lin Tan, Kalyan K. Bhattacharyya, Shamit K. Dutta, William R. Bamlet, Kari G. Rabe, Enfeng Wang, Thomas C. Smyrk, Ann L. Oberg, Gloria M. Petersen, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Objectives 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 G12D/+;Trp53 F2-10 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 3) and Met-3wk (median, 137.9 mm 3) groups was significantly lower than those in the control group (median, 481.1 mm 3; 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.

Original languageEnglish (US)
Pages (from-to)636-647
Number of pages12
JournalPancreas
Volume44
Issue number4
DOIs
StatePublished - May 25 2015

Keywords

  • chemoprevention
  • inflammation
  • metformin
  • pancreatic cancer

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Hepatology
  • Endocrinology

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