Background: JNK is constitutively activated in most hepatocellular carcinomas (HCC); yet, its exact role in carcinogenesis remains elusive. While TNF-related apoptosis inducing ligand (TRAIL) is known as a major mediator of acquired immune tumor surveillance, and is currently tested in clinical trials as a novel cancer therapy, the resistance of many tumors 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 be specifically responsible for resistance to apoptosis in these tumors.
Methods: The effect of JNK/Jun inhibition on receptor-mediated apoptosis was analyzed by pharmacologic inhibition or RNA-interference in cancer cells and non-tumor 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 sensitized 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: We shed new light on the role of JNK over-expression in HCC. Expression and TRAIL-dependent feedback activation of JNK likely represent a mechanism by which cancer cells escape TRAIL mediated tumorsurveillance. Thus, JNK inhibition represents a novel strategy for specifically sensitizing HCC cells TRAIL, and opens promising therapeutic perspectives for the safe and effective use of TRAIL in cancer therapy.