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Abstract
While accumulating evidence has shown that the use of the diabetic drug metformin may be beneficial against various tumors in some epidemiological studies, a few studies failed to show the same beneficial effects. The molecular and cellular mechanisms for these conflicting observations are not clear. In this study, we compared the inhibitory effects of cell growth by metformin on several hepatic tumor cell lines: SMMC-7721, HCC-97L, HCC-LM3 and HepG2. While metformin inhibited cell growth in all these cells, we found that SMMC-7721, HCC-97L and HCC-LM3 cells were more resistant than HepG2 cells. Mechanistically, we found that metformin inhibited mTOR in all these hepatic tumor cells. However, SMMC-7721 cells had higher levels of basal autophagy and mTORC2-mediated feedback activation of Akt than HepG2 cells, which may render SMMC-7721 cells to be more resistant to metformin-induced inhibition of cell growth. Similarly, HCC-97L and HCC-LM3 cells also had higher feedback activation of AKT than HepG2 cells, which may also account for their resistance to metformin-induced inhibition of cell growth. Therefore, the various basal autophagy and mTOR activity in different cancer cells may contribute to the controversial findings on the use of metformin in inhibition of cancers in humans.
Highlights
Hepatocellular carcinoma (HCC) is a major cancer that accounts for more than 600,000 deaths per year [1]
MG132, a proteasome inhibitor, markedly increased the number of apoptotic and propidium iodide (PI) positive secondary necrotic cells as well as caspase-3 activity in both 7721 and HepG2 cells HepG2 cells were more sensitive than 7721 cells in response to MG132. These results suggest that the reduced MTT values after metformin treatment in 7721 and HepG2 cells were mainly due to inhibition of cell growth
The reduced cell growth was more dramatic in metformintreated HepG2 cells than in 7721 cells, which is consistent with the MTT assay
Summary
Hepatocellular carcinoma (HCC) is a major cancer that accounts for more than 600,000 deaths per year [1]. HCC is very common in southeast Asia and Africa because of their high HBV infection rate. The incidence of HCC has increased in the US and western Europe over the past 25 years. The exact molecular pathogenesis of HCC is not yet well understood, PLOS ONE | DOI:10.1371/journal.pone.0130953. Autophagy and Akt Regulate Metformin-Induced Tumor Inhibition of General Medical Sciences of the National Institutes of Health (P20 GM103418), as well as National Natural Science Foundation of China (No 81030038, 81272389, J.F). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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