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Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway
- Source :
- International Journal of Oncology. 43:1503-1510
- Publication Year :
- 2013
- Publisher :
- Spandidos Publications, 2013.
-
Abstract
- The induction of senescence for cancer treatment has provoked considerable interest recently. Metformin, a first-line drug for diabetes mellitus type 2, appears to be associated with a lower risk and improved outcomes in hepatocellular carcinoma (HCC). The mechanism involved in function of metformin in HCC is poorly understood. We show that low doses of metformin induced hepatoma cell senescence characterized by accumulation of senescence-associated β-galactosidase activity (SA-β-gal) and the senescence marker Dec1, whereas the higher doses initiated apoptotic cell death. Metformin-induced senescence was accompanied by enhanced phosphorylation levels of AMP-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase (ACC). The expression of acetylated p53 at Lys382 (Ac-p53) and p21 was also increased, while phosphorylation of p53 at Ser15 (p-p53), p53, p16 and pRB was rarely altered after metformin treatment. Moreover, inhibition of AMPK decreased p-AMPK, p-ACC, Ac-p53 and p21 expression, diminished SA-β-gal staining and restored hepatoma cell proliferation. In addition, p53 siRNA transfection attenuated metformin-induced SA-β-gal staining. Intriguingly, co-expression of SIRT1 and p53 dramatically reduced the levels of Ac-p53, however, low doses of metformin treatment partially reversed the effect of SIRT1 on p53 acetylation and elevated SA-β-gal activity. These observations indicate that activation of the AMPK pathway promotes senescence in hepatoma cells exposed to low concentrations of metformin in a p53-dependent manner. Further, low doses of metformin may have the potential to be used as an adjuvant to HCC therapy.
- Subjects :
- Senescence
Cancer Research
medicine.medical_specialty
Carcinoma, Hepatocellular
endocrine system diseases
Blotting, Western
Cell
Apoptosis
Biology
Immunoenzyme Techniques
AMP-Activated Protein Kinase Kinases
Internal medicine
Tumor Cells, Cultured
medicine
Humans
Hypoglycemic Agents
RNA, Small Interfering
Protein kinase A
Cellular Senescence
Cell Proliferation
Dose-Response Relationship, Drug
Cell Cycle
Liver Neoplasms
AMPK
Transfection
Cell cycle
Metformin
medicine.anatomical_structure
Endocrinology
Oncology
Cancer research
Tumor Suppressor Protein p53
Protein Kinases
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 17912423 and 10196439
- Volume :
- 43
- Database :
- OpenAIRE
- Journal :
- International Journal of Oncology
- Accession number :
- edsair.doi.dedup.....82065454bf370417ba7c0a1259a890d2
- Full Text :
- https://doi.org/10.3892/ijo.2013.2077