Metformin inhibits TGF‑β1‑induced epithelial‑mesenchymal transition and liver metastasis of pancreatic cancer cells

  • Authors:
    • Juichiro Yoshida
    • Takeshi Ishikawa
    • Yuki Endo
    • Shinya Matsumura
    • Takayuki Ota
    • Katsura Mizushima
    • Yasuko Hirai
    • Kaname Oka
    • Tetsuya Okayama
    • Naoyuki Sakamoto
    • Ken Inoue
    • Kazuhiro Kamada
    • Kazuhiko Uchiyama
    • Tomohisa Takagi
    • Yuji Naito
    • Yoshito Itoh
  • View Affiliations

  • Published online on: April 23, 2020     https://doi.org/10.3892/or.2020.7595
  • Pages: 371-381
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Abstract

Epithelial‑mesenchymal transition (EMT) is considered a crucial event in the development of cancer metastasis. Metformin is a drug used in the treatment of type 2 diabetes. Recently, increasing evidence has indicated that metformin possesses anti‑tumor activities. However, the effects of metformin on EMT and metastases in pancreatic cancer remain unknown. Thus, the present study investigated whether metformin inhibits EMT of human pancreatic cancer cell lines. Pancreatic cancer cells were stimulated with transforming growth factor β1 (TGF‑β1), an activator of EMT signaling, with or without metformin. After 48 h, the levels of epithelial and mesenchymal markers were evaluated by western blot analysis, immunocytochemistry and RT‑qPCR. Cancer cell migration was evaluated by an in vitro wound healing assay. The cells stimulated with TGF‑β1 acquired an elongated and fusiform morphology, which was inhibited by metformin. The wound healing assay revealed that metformin significantly suppressed the TGF‑β1‑stimulated migration of pancreatic cancer cells. Following treatment with metformin, E‑cadherin expression (epithelial marker) was upregulated, and the levels of mesenchymal markers were downregulated, which had been increased by TGF‑β1 in these cells. Exposure of the cells to TGF‑β1 activated the Smad2/3 and Akt/mammalian target of rapamycin (mTOR) pathways, and this effect was inhibited by metformin, suggesting that metformin inhibits TGF‑β1‑induced‑EMT through the down‑regulation of the Smad pathway in PANC‑1 cells and the downregulation of the Akt/mTOR pathway in BxPC‑3 cells. In an animal model of surgical orthotopic implantation, metformin inhibited liver metastasis without a significant reduction in the size of the primary pancreatic tumor. On the whole, the findings of the present study suggest that metformin inhibits EMT and cancer metastasis through the Smad or Akt/mTOR pathway.
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July 2020
Volume 44 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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APA
Yoshida, J., Ishikawa, T., Endo, Y., Matsumura, S., Ota, T., Mizushima, K. ... Itoh, Y. (2020). Metformin inhibits TGF‑β1‑induced epithelial‑mesenchymal transition and liver metastasis of pancreatic cancer cells. Oncology Reports, 44, 371-381. https://doi.org/10.3892/or.2020.7595
MLA
Yoshida, J., Ishikawa, T., Endo, Y., Matsumura, S., Ota, T., Mizushima, K., Hirai, Y., Oka, K., Okayama, T., Sakamoto, N., Inoue, K., Kamada, K., Uchiyama, K., Takagi, T., Naito, Y., Itoh, Y."Metformin inhibits TGF‑β1‑induced epithelial‑mesenchymal transition and liver metastasis of pancreatic cancer cells". Oncology Reports 44.1 (2020): 371-381.
Chicago
Yoshida, J., Ishikawa, T., Endo, Y., Matsumura, S., Ota, T., Mizushima, K., Hirai, Y., Oka, K., Okayama, T., Sakamoto, N., Inoue, K., Kamada, K., Uchiyama, K., Takagi, T., Naito, Y., Itoh, Y."Metformin inhibits TGF‑β1‑induced epithelial‑mesenchymal transition and liver metastasis of pancreatic cancer cells". Oncology Reports 44, no. 1 (2020): 371-381. https://doi.org/10.3892/or.2020.7595