Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway

  • Authors:
    • Gao Yi
    • Zhimin He
    • Xinke Zhou
    • Lewu Xian
    • Taize Yuan
    • Xiaoting Jia
    • Jian Hong
    • Lu He
    • Jifang Liu
  • View Affiliations

  • Published online on: August 23, 2013     https://doi.org/10.3892/ijo.2013.2077
  • Pages: 1503-1510
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


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.
View Figures
View References

Related Articles

Journal Cover

November 2013
Volume 43 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Yi, G., He, Z., Zhou, X., Xian, L., Yuan, T., Jia, X. ... Liu, J. (2013). Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway. International Journal of Oncology, 43, 1503-1510. https://doi.org/10.3892/ijo.2013.2077
MLA
Yi, G., He, Z., Zhou, X., Xian, L., Yuan, T., Jia, X., Hong, J., He, L., Liu, J."Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway". International Journal of Oncology 43.5 (2013): 1503-1510.
Chicago
Yi, G., He, Z., Zhou, X., Xian, L., Yuan, T., Jia, X., Hong, J., He, L., Liu, J."Low concentration of metformin induces a p53-dependent senescence in hepatoma cells via activation of the AMPK pathway". International Journal of Oncology 43, no. 5 (2013): 1503-1510. https://doi.org/10.3892/ijo.2013.2077