title: P60-c-src suppresses apoptosis through inhibition of caspase 8 activation in hepatoma cells, but not in primary hepatocytes.
abstract: OBJECTIVE
  Failure to induce apoptosis triggered by members of the death receptor family has been described in hepatocellular carcinoma (HCC) and sensitization of malignant cells to pro-apoptotic molecules such as TRAIL has been proposed as an alternative cancer therapy. Limiting to this approach are the resistance of many tumor cells to TRAIL and safety concerns about the toxicity of TRAIL in normal hepatocytes.
  
  
  METHODS
  We here explored the possibility that the protooncogene c-Src, known to be overexpressed in a variety of tumors, could be specifically responsible for the loss of response to receptor-mediated apoptosis.
  
  
  RESULTS
  Cotreatment of several hepatoma cell lines with the Src inhibitor PP2 potently sensitized these cells to TRAIL and CD95, dramatically decreasing effective doses of TRAIL to as low as 1 ng/ml. Remarkably, Src-inhibition did not synergize with TRAIL signaling in primary hepatocytes. Specific siRNAs showed that the effect was due to blockade of p60(c-Src) and occurred through increased recruitment of caspase 8.
  
  
  CONCLUSIONS
  We provide evidence that p60(c-Src) is an important and effective suppressor of receptor-mediated apoptosis in hepatoma cells but not in primary human hepatocytes. Inhibition of Src sensitizes tumor cells to apoptosis and decreases effective doses of TRAIL to therapeutic concentrations.
authors.affiliation: Ludwig-Maximilians-University, University Hospital Grosshadern, Department of Medicine 2, Research Lab B 5 E01 308, Marchioninistrasse 15, D-81377 Munich, Germany. enrico.detoni@med.uni-muenchen.de
authors.forename: Enrico N
authors.initials: EN
authors.lastname: De Toni
authors.forename: Christian
authors.initials: C
authors.lastname: Kuntzen
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Gerbes
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Sonuc
authors.forename: Simon R
authors.initials: SR
authors.lastname: Mucha
authors.forename: Peter
authors.initials: P
authors.lastname: Camaj
authors.forename: Christiane
authors.initials: C
authors.lastname: Bruns
authors.forename: Burkhard
authors.initials: B
authors.lastname: Göke
authors.forename: Sören T
authors.initials: ST
authors.lastname: Eichhorst
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000503:physiopathology*; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005838:Genotype; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology / Q000503:physiopathology*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D019014:fas Receptor / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
chemical_list: C412373:AG 1879; D061945:Caspase Inhibitors; D011743:Pyrimidines; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D053221:TNF-Related Apoptosis-Inducing Ligand; D019014:fas Receptor; D016392:Proto-Oncogene Proteins pp60(c-src); D019061:src-Family Kinases; D053181:Caspase 8