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Metformin Promotes Apoptosis but Suppresses Autophagy in Glucose-Deprived H4IIE Hepatocellular Carcinoma Cells.

ABSTRACT: Metformin, a well-known anti-diabetic drug, has gained interest due to its association with the reduction of the prevalence of cancer in patients with type 2 diabetes and the anti-proliferative effect of metformin in several cancer cells. Here, we investigated the anti-proliferative effect of metformin with respect to apoptosis and autophagy in H4IIE hepatocellular carcinoma cells.H4IIE rat cells were treated with metformin in glucose-free medium for 24 hours and were then subjected to experiments examining the onset of apoptosis and/or autophagy as well as the related signaling pathways.When H4IIE cells were incubated in glucose-free media for 24 hours, metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) reduced the viability of cells. Inhibition of AMP-activated protein kinase (AMPK) by compound C significantly blocked cell death induced by metformin or AICAR. Pro-apoptotic events (nuclear condensation, hydrolysis of intact poly ADP ribose polymerase and caspase-3) were stimulated by metformin and then suppressed by compound C. Interestingly, the formation of acidic intracellular vesicles, a marker of autophagy, was stimulated by compound C. Although the deprivation of amino acids in culture media also induced apoptosis, neither metformin nor compound C affected cell viability. The expression levels of all of the autophagy-related proteins examined decreased with metformin, and two proteins (light chain 3 and beclin-1) were sensitive to compound C. Among the tested inhibitors against MAP kinases and phosphatidylinositol-3-kinase/mammalian target of rapamycin, SB202190 (against p38MAP kinase) significantly interrupted the effects of metformin.Our data suggest that metformin induces apoptosis, but suppresses autophagy, in hepatocellular carcinoma cells via signaling pathways, including AMPK and p38 mitogen-activated protein kinase.

SUBMITTER: Park DB

PROVIDER: S-EPMC4696989 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Metformin Promotes Apoptosis but Suppresses Autophagy in Glucose-Deprived H4IIE Hepatocellular Carcinoma Cells.

Park Deok Bae DB

Diabetes & metabolism journal 20151201 6

<h4>Background</h4>Metformin, a well-known anti-diabetic drug, has gained interest due to its association with the reduction of the prevalence of cancer in patients with type 2 diabetes and the anti-proliferative effect of metformin in several cancer cells. Here, we investigated the anti-proliferative effect of metformin with respect to apoptosis and autophagy in H4IIE hepatocellular carcinoma cells.<h4>Methods</h4>H4IIE rat cells were treated with metformin in glucose-free medium for 24 hours a ...[more]

PMID: 26706918

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Project description:BackgroundPeripheral serotonin is involved in tumorigenesis and induces a pro-proliferative effect in hepatocellular carcinoma (HCC) cells; however, the intracellular mechanisms by which serotonin exerts a mitogenic effect remain unclear. In this research, we examined whether FOXO3a, a transcription factor at the interface of crucial cellular processes, plays a role downstream of serotonin in HCC cells.ResultsThe cell viability and expression of FOXO3a was assessed in three HCC cell lines (Huh7, HepG2 and Hep3B) during serum deprivation in the presence or absence of serotonin. Serum free media significantly inhibited HCC proliferation and led to reduced expression and nuclear accumulation of FOXO3a. Knockdown of FOXO3a enhanced the ability of serum deprivation to inhibit HCC cells proliferation. And overexpression of non-phosphorylated FOXO3a in HCC cells reversed serum-deprivation-induced growth inhibition. Serotonin reversed the serum-deprivation-induced inhibition of cell proliferation and upregulated FOXO3a in Huh7 cells; however, serotonin had no effect on the proliferation of serum-deprived HepG2 or Hep3B cells. In addition to proliferation, serotonin also induced phosphorylation of AKT and FOXO3a in serum-deprived Huh7 cells but not in HepG2 and Hep3B cells. However, the phosphorylation of FOXO3a induced by serotonin did not export FOXO3a from nucleus to cytoplasm in serum-deprived Huh7 cells. Consequently, we demonstrated that serotonin promoted the proliferation of Huh7 cells by increasing the expression of FOXO3a. We also provide preliminary evidence that different expression levels of the 5-HT2B receptor (5-HT2BR) may contribute to the distinct effects of serotonin in different serum-deprived HCC cells.ConclusionsThis study demonstrates that FOXO3a functions as a growth factor in serum-deprived HCC cells and serotonin promotes the proliferation of serum-deprived HCC cells via upregulation of FOXO3a, in the presence of sufficient levels of the serotonin receptor 5-HT2BR. Drugs targeting the serotonin-5-HT2BR-FOXO3a pathway may provide a novel target for anticancer therapy.

Dataset Information

Metformin Promotes Apoptosis but Suppresses Autophagy in Glucose-Deprived H4IIE Hepatocellular Carcinoma Cells.

Publications

Metformin Promotes Apoptosis but Suppresses Autophagy in Glucose-Deprived H4IIE Hepatocellular Carcinoma Cells.

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