title: Reduced tumor growth in vivo and increased c-Abl activity in PC3 prostate cancer cells overexpressing the Shb adapter protein.
abstract: BACKGROUND
  Induction of apoptosis is one strategy for treatment of prostate cancer. The Shb adapter protein has been found to regulate apoptosis in various cell types and consequently human prostate cancer 3 (PC3) cells were transfected to obtain cells overexpressing Shb in order to increase our understanding of the mechanisms regulating PC3 cell apoptosis.
  
  
  METHODS
  Human prostate cancer cells (PC3) were transfected with control vector or a vector containing the Shb cDNA. Clones overexpressing Shb were studied with respect to apoptosis (Dapi, M30) and c-Abl activation (Western blot for pY-245-Abl). The cells were exposed to the anti-tumor agent 2-methoxyestradiol (2-ME) and the p38 MAPK and c-Abl inhibitors SB203580 and STI-571, respectively, after which cell death was determined. In vivo tumor growth and tumor cell proliferation (Ki-67 staining) or apoptosis (active caspase 3 staining) were also determined in nude mice.
  
  
  RESULTS
  PC3 cells overexpressing Shb exhibited increased rates of apoptosis in the presence of the anti-tumor agent 2-ME. The Shb cells displayed increased activity of the pro-apoptotic kinase c-Abl. Pre-treatment with p38 MAPK (SB203580) or c-Abl (STI-571) inhibitors completely blocked 2-ME-induced apoptosis, implicating these two pathways in the response. The PC3-Shb cells displayed reduced tumor growth in vivo, an effect occurring as a consequence of increased apoptosis and reduced DNA synthesis.
  
  
  CONCLUSIONS
  It is concluded that Shb promotes 2-ME-induced PC3 cell apoptosis by increased pro-apoptotic signaling via the c-Abl pathway and that this causes reduced tumor growth in vivo.
authors: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. padideh.davoodpour@ki.se <padideh.davoodpour@ki.se>
authors: Padideh
authors: P
authors: Davoodpour
authors: Maréne
authors: M
authors: Landström
authors: Michael
authors: M
authors: Welsh
mesh_terms: D000077584:2-Methoxyestradiol; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D050257:Tubulin Modulators / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; C490081:SHB protein, human; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D016315:Proto-Oncogene Proteins c-abl; D048051:p38 Mitogen-Activated Protein Kinases
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