Metformin Promotes Apoptosis but Suppresses Autophagy in Glucose-Deprived H4IIE Hepatocellular Carcinoma Cells
Diabetes & Metabolism Journal
;
: 518-527, 2015.
Article
in English
| WPRIM
| ID: wpr-149420
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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Phosphotransferases
/
Protein Kinases
/
Autophagy
/
Cell Survival
/
Prevalence
/
Cell Death
/
Poly(ADP-ribose) Polymerases
/
Apoptosis
/
Carcinoma, Hepatocellular
/
Sirolimus
Type of study:
Prevalence study
Limits:
Animals
/
Humans
Language:
English
Journal:
Diabetes & Metabolism Journal
Year:
2015
Type:
Article
Similar
MEDLINE
...
LILACS
LIS