JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand.
BACKGROUND
cJun terminal kinase (JNK) is constitutively activated in most hepatocellular carcinomas (HCCs), yet its exact role in carcinogenesis remains controversial. While tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a major mediator of acquired immune tumour surveillance, and is currently being tested in clinical trials as a novel cancer therapy, the resistance of many tumours to TRAIL and concerns about its toxicity in vivo represent obstacles to its clinical application. In this study we investigated whether JNK activity in HCC could contribute to the resistance to apoptosis in these tumours.


METHODS
The effect of JNK/Jun inhibition on receptor-mediated apoptosis was analysed by pharmacological inhibition or RNA interference in cancer cells and non-tumour cells isolated from human liver or transgenic mice lacking a phosphorylation site for Jun.


RESULTS
JNK inhibition caused cell cycle arrest, enhanced caspase recruitment, and greatly sensitised HCC cells but not normal hepatocytes to TRAIL. TRAIL-induced activation of JNK could be effectively interrupted by administration of the JNK inhibitor SP600125.


CONCLUSIONS
Expression and TRAIL-dependent feedback activation of JNK likely represent a mechanism by which cancer cells escape TRAIL-mediated tumour surveillance. JNK inhibition might represent a novel strategy for specifically sensitising HCC cells to TRAIL thus opening promising therapeutic perspectives for safe and effective use of TRAIL in cancer treatment.
Mucha
S R
SR
University of Munich, University Hospital Grosshadern, Department of Medicine II, Research Lab B 5 E01 308, Marchioninistrasse 15, D-81377 Munich, Germany.
Rizzani
A
A
Gerbes
A L
AL
Camaj
P
P
Thasler
W E
WE
Bruns
C J
CJ
Eichhorst
S T
ST
Gallmeier
E
E
Kolligs
F T
FT
Göke
B
B
De Toni
E N
EN
D000818:Animals; D000873:Anthracenes / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000627:therapeutic use; D019014:fas Receptor / Q000378:metabolism
D000873:Anthracenes; D051017:Apoptosis Regulatory Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D019014:fas Receptor; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases