Journal Articles

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

July 28, 2015

p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cellsBiochem Biophys Res Commun. 2015 Jul 28, Li P1, Zhao M2, Parris AB2, Feng X3, Yang X4.

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

Copyright © 2015 Elsevier Inc. All rights reserved.

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