P60-c-src suppresses apoptosis through inhibition of caspase 8 activation in hepatoma cells, but not in primary hepatocytes.
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.
De Toni
Enrico N
EN
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
Kuntzen
Christian
C
Gerbes
Alexander L
AL
Thasler
Wolfgang E
WE
Sonuc
Nilüfer
N
Mucha
Simon R
SR
Camaj
Peter
P
Bruns
Christiane
C
Göke
Burkhard
B
Eichhorst
Sören T
ST
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
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