Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells

• Published in: PloS one Vol. 10; no. 6; p. e0131207
• Main Authors: Liu, Zhao, Ren, Lidong, Liu, Chenghao, Xia, Tiansong, Zha, Xiaoming, Wang, Shui
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.06.2015; Public Library of Science (PLoS)
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Biotechnology; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - physiopathology; Cancer; Cancer cells; Cell cycle; Cell Cycle - drug effects; Cell death; Cell growth; Cell migration; Diabetes; Disease prevention; Epithelial-Mesenchymal Transition - drug effects; Extracellular signal-regulated kinase; Female; Health aspects; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Kinases; Laboratory animals; MAP kinase; MAP Kinase Signaling System - drug effects; MCF-7 Cells; Medical research; Mesenchyme; Metabolic pathways; Metabolism; Metastases; Metformin; Mice; Mice, Inbred BALB C; Mice, Nude; Mortality; Oncology; Pathways; Phenformin - pharmacology; Phenformin - therapeutic use; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Standard error; Stem cells; Surgery; TOR protein; TOR Serine-Threonine Kinases - metabolism; Tumor cell lines; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0131207

Breast cancer remains a world-wide challenge, and additional anti-cancer therapies are still urgently needed. Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin. However, little attention has been given to the role of phenformin in breast cancer. In this study, we reveal the role of phenformin in cell death of the MCF7, ZR-75-1, MDA-MB-231 and SUM1315 breast cancer cell lines. The respective IC50 values of phenformin in MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were 1.184±0.045 mM, 0.665±0.007 mM, 2.347±0.010 mM and 1.885±0.015 mM (mean± standard error). Phenformin induced cell cycle change and apoptosis in breast cancer cells via the AMPK/mTOR/p70s6k and MAPK/ERK pathways. Interestingly, phenformin induced MET (mesenchymal-epithelial transition) and decreased the migration rate in breast cancer cell lines. Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice. Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti-cancer activity in breast cancer.