title: Contributions of AMPK and p53 dependent signaling to radiation response in the presence of metformin.
abstract: OBJECTIVE
  Metformin is commonly prescribed to treat type 2 diabetes, and has additional potential as a cancer prophylactic and therapeutic. Metformin activates AMPK that in turn can launch a p53-dependent metabolic checkpoint. Possible interactions between metformin and radiation are poorly understood. Since radiation-induced signaling also involves AMPK and p53, we investigated their importance in mediating responses to metformin and radiation.
  
  
  METHODS
  A549 cells, HCT116 cells wildtype or knockout for p53 or MEFs wildtype or double knockout for AMPKα1 and α2 were irradiated in the presence or absence of metformin. The impact of metformin on oxygen consumption and proliferation rates was determined, as well as clonogenic radiation survival.
  
  
  RESULTS
  Metformin resulted in moderate radiation protection in all cell lines, irrespective of AMPK and p53. Loss of AMPK sensitized cells to the anti-proliferative effects of metformin, while loss of p53 promoted both the growth inhibitory and toxic effects of metformin. Consequently, overall cell death after radiation was similar with and without metformin irrespective of AMPK or p53 genotype.
  
  
  CONCLUSIONS
  The anti-proliferative activity of metformin may confer benefit in combination with radiotherapy, and this benefit is intensified upon loss of AMPK or p53 signaling.
authors.affiliation: Ontario Cancer Institute and Campbell Family Institute for Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada; Faculty of Medicine, University of Toronto, Canada.
authors.forename: Hala
authors.initials: H
authors.lastname: Muaddi
authors.forename: Sanjana
authors.initials: S
authors.lastname: Chowdhury
authors.forename: Ravi
authors.initials: R
authors.lastname: Vellanki
authors.forename: Paul
authors.initials: P
authors.lastname: Zamiara
authors.forename: Marianne
authors.initials: M
authors.lastname: Koritzinsky
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Metformin; Proliferation; Radiosensitivity; p53