title: Etoposide induces cell death via mitochondrial-dependent actions of p53.
abstract: BACKGROUND
  Etoposide has been used clinically in cancer treatment, as well as in numerous research studies, for many years. However, there is incomplete information about its exact mechanism of action in induction of cell death.
  
  
  METHODS
  Etoposide was compared at various concentrations to characterize the mechanisms by which it induces cell death. We investigated its effects on mouse embryonic fibroblasts (MEFs) and focused on both transcriptional and non-transcriptional responses of p53.
  
  
  RESULTS
  Here we demonstrate that treatment of MEFs with higher concentrations of etoposide induce apoptosis and activate the transcription-dependent functions of p53. Interestingly, lower concentrations of etoposide also induced apoptosis, but without any evidence of p53-dependent transcription up-regulation. Treatment of MEFs with an inhibitor of p53, Pifithrin-α, blocked p53-dependent transcription but failed to rescue the cells from etoposide-induced apoptosis. Treatment with PES, which inhibits the mitochondrial arm of the p53 pathway inhibited etoposide-induced cell death at all concentrations tested.
  
  
  CONCLUSIONS
  We have demonstrated that transcriptional functions of p53 are dispensable for etoposide-induced cell death. The more recently characterized effects of p53 at the mitochondria, likely involving its interactions with BCL-2 family members, are thus more important for etoposide's actions.
authors.affiliation: Department of Medicine, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 2660 Oak St., Vancouver, BC V6H 3Z6 Canada.
authors.forename: Sarwat
authors.initials: S
authors.lastname: Jamil
authors.affiliation: Department of Medicine, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 2660 Oak St., Vancouver, BC V6H 3Z6 Canada.
authors.forename: Irene
authors.initials: I
authors.lastname: Lam
authors.affiliation: Department of Medicine, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 2660 Oak St., Vancouver, BC V6H 3Z6 Canada.
authors.forename: Maryam
authors.initials: M
authors.lastname: Majd
authors.affiliation: Department of Medicine, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 2660 Oak St., Vancouver, BC V6H 3Z6 Canada.
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Tsai
authors.affiliation: Department of Medicine, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 2660 Oak St., Vancouver, BC V6H 3Z6 Canada.
authors.forename: Vincent
authors.initials: V
authors.lastname: Duronio
keywords: DNA damage; Fibroblast; Mitochondria; P53 acetylation; Transcription