Research Article: Metformin inhibits gastric cancer cells metastatic traits through suppression of epithelial-mesenchymal transition in a glucose-independent manner

Date Published: March 23, 2017

Publisher: Public Library of Science

Author(s): Shiva Valaee, Mohammad Mehdi Yaghoobi, Mehdi Shamsara, Aamir Ahmad.

http://doi.org/10.1371/journal.pone.0174486

Abstract

Epithelial-mesenchymal transition (EMT), which is mainly recognized by upregulation of mesenchymal markers and movement of cells, is a critical stage occurred during embryo development and spreading cancerous cells. Metformin is an antidiabetic drug used in treatment of type 2 diabetes. EMT inhibitory effect of metformin has been studied in several cancers; however, it remains unknown in gastric cancer. The aim of the present study was to investigate the metformin effects on inhibition of EMT-related genes as well as migration and invasion of AGS gastric cancer cell line. Moreover, to study the effect of glucose on metformin-mediated EMT inhibition, all experiments were performed in two glucose levels, similar to non-fasting blood sugar (7.8 mM) and hyperglycemic (17.5 mM) conditions. The results showed reduction of mesenchymal markers, including vimentin and β-catenin, and induction of epithelial marker, E-cadherin, by metformin in both glucose concentrations. Furthermore, wound-healing and invasion assays showed a significant decrease in cell migration and invasion after metformin treatment in both glucose levels. In conclusion, our results indicated that metformin strongly inhibited EMT of gastric cancer cells in conditions mimicking normo and hyperglycemic blood sugar.

Partial Text

Gastric cancer is the second leading cause of cancer-related mortality in the world [1]. This high mortality rate arises from that a large number of patients are diagnosed at the advanced stages of gastric cancer when the tumor metastasis has been occurred. While detection of gastric cancer in early stages before its spread generally extends survival rate up to five-year higher.

Upregulation of EMT markers in cancers play a critical role in cell invasion and cancer metastasis [19–22]. Hence, EMT inhibition is considered as a pivotal therapeutic step in cancers treatment. A number of studies refer to anti-proliferation and anti-metastatic effects of metformin on several cancers [23, 24]. However, the adverse effects of metformin on gastric cancer remain obscure. The aim of the present study was to investigate the effect of glucose levels on metformin-mediated inhibition of EMT in human gastric cell line. For this purpose, the AGS cells were cultured in glucose concentrations of 7.8 and 17.5 mM and treated with 10 mM metformin. We found that metformin suppressed cell migration and invasion in both glucose conditions in a time-dependent manner, such that the strongest repression was observed in 72-hour treatments. Further analyses revealed the induction of E-cadherin (epithelial marker) and the reduction of β-catenin and vimentin (EMT markers). Furthermore, the metformin anti-EMT activity was similar in the both glucose concentrations.

 

Source:

http://doi.org/10.1371/journal.pone.0174486

 

0 0 vote
Article Rating
Subscribe
Notify of
guest
0 Comments
Inline Feedbacks
View all comments