title: p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells.
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.
authors.affiliation: 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.
authors.forename: Puyu
authors.initials: P
authors.lastname: Li
authors.affiliation: JLC Biomedical/Biotechnology Research Institute, Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: JLC Biomedical/Biotechnology Research Institute, Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Parris
authors.affiliation: Department of Oncology, Cancer Institute, First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471003, PR China. Electronic address: samfeng137@hotmail.com.
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Feng
authors.affiliation: JLC Biomedical/Biotechnology Research Institute, Department of Biology, North Carolina Central University, Kannapolis, NC 28081, USA. Electronic address: xyang@nccu.edu.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D061986:MCF-7 Cells; D008687:Metformin / Q000008:administration & dosage*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D008687:Metformin
keywords: Breast cancer; CP/31398; Metformin; Nutlin-3α; Phenformin; p53