Metformin-induced killing of liver initiating cells by inhibiting the PI3K/Akt pathway
Objective To investigate the effect of metformin on self-renewal of hepatocellular carcinoma cells and its potential mechanism.Methods The effect of metformin on self-renewal of hepatocellular carcinoma cells in vitro was examined by pellet forming experiment and cell culture in vitro.The apoptosis of cells treated with sorafenib was compared between metformin and DMSO.After SMMC-7721 cells were treated with metformin,the mRNA expression levels of CD90,CD133 and Sox2 were detected by Real-time PCR,and the protein expressions of p-Akt and p-mTOR were detected by Western blot.The effects of metformin on NOD/SCID mice injected with SMMC-7721 were studied in animal model.Results Metformin reduced the proportion of tumor stem cells in liver cancer cells.After sorafenib treatment,the apoptosis rate of SMMC-7721-metformin group was significantly higher than SMMC-771-DMSO group.SMMC-7721 cells were treated with metformin,and the expressions of CD90,CD 133 and Sox2 were significantly down-regulated.Metformin significantly reduced the pelletizing ability of hepatocellular carcinoma cells.In addition,the PI3K/Akt pathway was down-regulated in metformin-treated SMMC-7721 cells,and blocking the PI3K/Akt pathway reduced the inhibitory ability of metformin on the cells.Conclusion Metformin plays an important role in HCC tumor-initiating cells through PI3K/Akt signaling and may be a promising therapeutic drug for HCC patients.
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