Metformin suppresses the invasive ability of pancreatic cancer cells by blocking autocrine TGF-ß1 signaling

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive neoplasm with a 5-year survival rate of <8%. Metformin, the most widely used antidiabetic drug in the world, has been shown to exert anticancer activities in epidemiological and animal studies. Our previous studies revealed that metformin suppressed desmoplasia in PDAC by reducing TGF-ß1 production in cancer cells. The aim of the present study was to investigate the effects of metformin on invasion and epithelial-mesenchymal transition (EMT) in pancreatic cancer and to reveal the underlying mechanisms. In the present study, we revealed that metformin suppressed migration, invasion and EMT changes in pancreatic cancer cells. Furthermore, metformin reduced TGF-ß1 production and Smad2/3 phosphorylation in pancreatic cancer cells. In addition, treatment with recombinant TGF-ß1 recovered the metformin-mediated invasion inhibition and EMT changes. Treatment with metformin also suppressed tumor growth, invasion and EMT in LSL-Kras^{G12D /+}, Trp53^{fl /+}and Pdx1-Cre (KPC) transgenic mice that harbor spontaneous pancreatic cancer. Collectively, our study revealed a new possible mechanism for the antitumor effects of metformin via autocrine TGF-ß1/Smad2/3 signaling in PDAC.