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

Abstract
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.
AuthorsZhao Liu, Lidong Ren, Chenghao Liu, Tiansong Xia, Xiaoming Zha, Shui Wang
JournalPloS one (PLoS One) Vol. 10 Issue 6 Pg. e0131207 ( 2015) ISSN: 1932-6203 [Electronic] United States
PMID26114294 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Hypoglycemic Agents
  • Phenformin
  • MTOR protein, human
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
Topics
  • AMP-Activated Protein Kinases (metabolism)
  • Animals
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Breast Neoplasms (metabolism, pathology, physiopathology)
  • Cell Cycle (drug effects)
  • Epithelial-Mesenchymal Transition (drug effects)
  • Female
  • Humans
  • Hypoglycemic Agents (pharmacology, therapeutic use)
  • MAP Kinase Signaling System (drug effects)
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phenformin (pharmacology, therapeutic use)
  • Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
  • TOR Serine-Threonine Kinases (metabolism)
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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