title: Erythropoietin-driven signalling and cell migration mediated by polyADP-ribosylation.
abstract: BACKGROUND
  Recombinant human erythropoietin (EPO) is the leading biotechnology engineered hormone for treatment of anaemia associated with chronic conditions including kidney failure and cancer. The finding of EPO receptors on cancer cells has raised the concern that in addition to its action in erythropoiesis, EPO may promote tumour cell growth. We questioned whether EPO-induced signalling and consequent malignant cell manifestation is mediated by polyADP-ribosylation.
  
  
  METHODS
  Erythropoietin-mediated PARP (polyADP-ribose polymerase-1) activation, gene expression and core histone H4 acetylation were examined in UT7 cells, using western blot analysis, RT-PCR and immunofluorescence. Erythropoietin-driven migration of the human breast epithelial cell line MDA-MB-435 was determined by the scratch assay and in migration chambers.
  
  
  RESULTS
  We have found that EPO treatment induced PARP activation. Moreover, EPO-driven c-fos and Egr-1 gene expression as well as histone H4 acetylation were mediated via polyADP-ribosylation. Erythropoietin-induced cell migration was blocked by the PARP inhibitor, ABT-888, indicating an essential role for polyADP-ribosylation in this process.
  
  
  CONCLUSIONS
  We have identified a novel pathway by which EPO-induced gene expression and breast cancer cell migration are regulated by polyADP-ribosylation. This study introduces new possibilities regarding EPO treatment for cancer-associated anaemia where combining systemic EPO treatment with targeted administration of PARP inhibitors to the tumour may allow safe treatment with EPO, minimising its possible undesirable proliferative effects on the tumour.
authors.affiliation: Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Inbar
authors.forename: M
authors.initials: M
authors.lastname: Cohen-Armon
authors.forename: D
authors.initials: D
authors.lastname: Neumann
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000494:pharmacology*; D006397:Hematinics / Q000494:pharmacology*; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D006397:Hematinics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases