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

被引:56
作者
Li, Puyu [1 ,2 ]
Zhao, Ming [1 ]
Parris, Amanda B. [1 ]
Feng, Xiaoshan [2 ]
Yang, Xiaohe [1 ]
机构
[1] N Carolina Cent Univ, Dept Biol, JLC Biomed Biotechnol Res Inst, Kannapolis, NC 28081 USA
[2] Henan Univ Sci & Technol, Affiliated Hosp 1, Inst Canc, Dept Oncol, Luoyang 471003, Peoples R China
关键词
Metformin; Phenformin; p53; Nutlin-3; alpha; CP/31398; Breast cancer; IN-VIVO; COMBINATION; METABOLISM; ACTIVATION; AMPK;
D O I
10.1016/j.bbrc.2015.07.117
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-3 alpha 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-3 alpha and CP/31398, is a promising strategy for improving metformin-mediated anti-cancer therapy, especially for tumors with p53 mutations. (C) 2015 Elsevier Inc. All rights reserved.
引用
收藏
页码:1267 / 1274
页数:8
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