Mucha, Simon R.; Rizzani, Antonia; Gerbes, Alexander L.; Camaj, Peter; Thasler, Wolfgang E.; Bruns, Christiane; Eichhorst, Sören T.; Gallmeier, Eike; Kolligs, Frank T.; Göke, Burkhard; De Toni, Enrico
JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand.
In: Gut, Vol. 58: pp. 688-698
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 apoptosisinducing
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 receptormediated
apoptosis was analysed by pharmacological
inhibition or RNA interference in cancer cells and nontumour
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. TRAILinduced
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.