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 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.