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 Christopher Smyrk, Ann L Oberg, Gloria M Petersen, Debabrata Mukhopadhyay

Research output: Contribution to journalArticle

26 Citations (Scopus)

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

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Metformin
Tumor Burden
Growth
Neoplasms
Carcinogenesis
Sp1 Transcription Factor
STAT3 Transcription Factor
Angiogenesis Inhibitors
Euthanasia
Pancreatic Neoplasms
Anti-Inflammatory Agents
Western Blotting
Immunohistochemistry
Phosphorylation
Polymerase Chain Reaction
Control Groups
Injections
Genes

Keywords

  • chemoprevention
  • inflammation
  • metformin
  • pancreatic cancer

ASJC Scopus subject areas

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

Cite this

Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling. / Tan, Xiang Lin; Bhattacharyya, Kalyan K.; Dutta, Shamit K.; Bamlet, William R.; Rabe, Kari G.; Wang, Enfeng; Smyrk, Thomas Christopher; Oberg, Ann L; Petersen, Gloria M; Mukhopadhyay, Debabrata.

In: Pancreas, Vol. 44, No. 4, 25.05.2015, p. 636-647.

Research output: Contribution to journalArticle

Tan XL, Bhattacharyya KK, Dutta SK, Bamlet WR, Rabe KG, Wang E et al. Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling. Pancreas. 2015 May 25;44(4):636-647. https://doi.org/10.1097/MPA.0000000000000308
Tan, Xiang Lin ; Bhattacharyya, Kalyan K. ; Dutta, Shamit K. ; Bamlet, William R. ; Rabe, Kari G. ; Wang, Enfeng ; Smyrk, Thomas Christopher ; Oberg, Ann L ; Petersen, Gloria M ; Mukhopadhyay, Debabrata. / Metformin suppresses pancreatic tumor growth with inhibition of NFκB/STAT3 inflammatory signaling. In: Pancreas. 2015 ; Vol. 44, No. 4. pp. 636-647.
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N2 - 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.

AB - 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.

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