Metformin Exerts Antiproliferative and Anti-metastatic Effects Against Cholangiocarcinoma Cells by Targeting STAT3 and NF-ĸB

Abstract

Background/Aim: Cholangiocarcinoma (CCA) is an aggressive cancer for which standard treatments are still ineffective. This study demonstrated the antiproliferative and anti-metastatic activity of metformin, an anti-diabetic drug, in CCA cells. Materials and Methods: Cell proliferation, migration/invasion and anoikis resistance were determined. The underlying mechanisms were identified using western blotting and immunocytofluorescence. Results: Metformin significantly suppressed proliferation of CCA cells in a dose- and time-dependent manner, regardless of glucose present in the medium. A low dose of metformin significantly increased anoikis and inhibited migration/ invasion of CCA cells that was in concert with the decrease of vimentin, matrix metalloproteinase (MMP)-2 and -7. Activation of 5’ adenosine monophosphate-activated protein kinase (AMPK) by phosphorylation together with suppression of nuclear translocation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-ĸB) were the underlying mechanisms for these effects. Conclusion: Metformin is a potent antiproliferative and anti-metastatic agent against human CCA cells. These findings encourage the repurposing of metformin in clinical trials to improve CCA treatment.