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Biochem Biophys Res Commun. 2015 Sep 4;464(4):1267-1274. doi: 10.1016/j.bbrc.2015.07.117. Epub 2015 Jul 28.

p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells.

Author information

1
JLC Biomedical/Biotechnology Research Institute, Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA; Department of Oncology, Cancer Institute, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, PR China.
2
JLC Biomedical/Biotechnology Research Institute, Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA.
3
Department of Oncology, Cancer Institute, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, PR China. Electronic address: samfeng137@hotmail.com.
4
JLC Biomedical/Biotechnology Research Institute, Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA. Electronic address: xyang@nccu.edu.

Abstract

The p53 tumor repressor gene is commonly mutated in human cancers. The tumor inhibitory effect of metformin on p53-mutated breast cancer cells remains unclear. Data from the present study demonstrated that p53 knockdown or mutation has a negative effect on metformin or phenformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. We also found that p53 reactivating agent nutlin-3α and CP/31398 promoted metformin-induced growth inhibition, senescence and apoptosis in MCF-7 (wt p53) and MDA-MB-231 (mt p53) cells, respectively. Treatment of MCF-7 cells with metformin or phenformin induced increase in p53 protein levels and the transcription of its downstream target genes, Bax and p21, in a dose-dependent manner. Moreover, we demonstrated that AMPK-mTOR signaling played a role in metformin-induced p53 up-regulation. The present study showed that p53 is required for metformin or phenformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. The combination of metformin with p53 reactivating agents, like nutlin-3α and CP/31398, is a promising strategy for improving metformin-mediated anti-cancer therapy, especially for tumors with p53 mutations.

KEYWORDS:

Breast cancer; CP/31398; Metformin; Nutlin-3α; Phenformin; p53

PMID:
26225749
DOI:
10.1016/j.bbrc.2015.07.117
[Indexed for MEDLINE]

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