Metformin Promotes Apoptosis but Suppresses Autophagy in Glucose-Deprived H4IIE Hepatocellular Carcinoma Cells.
10.4093/dmj.2015.39.6.518
- Author:
Deok Bae PARK
1
Author Information
1. Department of Histology and Institute of Medical Science, Jeju National University School of Medicine, Jeju, Korea. parkdb@jejunu.ac.kr
- Publication Type:Original Article
- Keywords:
Apoptosis;
Autophagy;
H4IIE hepatocellular carcinoma cells;
Metformin
- MeSH:
Amino Acids;
AMP-Activated Protein Kinases;
Animals;
Apoptosis*;
Autophagy*;
Carcinoma, Hepatocellular*;
Cell Death;
Cell Survival;
Culture Media;
Humans;
Hydrolysis;
Metformin*;
Phosphotransferases;
Poly(ADP-ribose) Polymerases;
Prevalence;
Protein Kinases;
Rats;
Sirolimus
- From:Diabetes & Metabolism Journal
2015;39(6):518-527
- CountryRepublic of Korea
- Language:English
-
Abstract:
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
