JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand

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 surveillanc...

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Bibliographic Details
Published in:	Gut Vol. 58; no. 5; p. 688
Main Authors:	Mucha, S R, Rizzani, A, Gerbes, A L, Camaj, P, Thasler, W E, Bruns, C J, Eichhorst, S T, Gallmeier, E, Kolligs, F T, Göke, B, De Toni, E N
Format:	Journal Article
Language:	English
Published:	England 01-05-2009
Subjects:	Animals Anthracenes - therapeutic use Apoptosis - drug effects Apoptosis - genetics Apoptosis Regulatory Proteins - drug effects Apoptosis Regulatory Proteins - genetics Blotting, Western Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - genetics Caspases - metabolism Cell Cycle - genetics Cell Line, Tumor Enzyme Activation fas Receptor - metabolism Gene Expression Regulation, Neoplastic Humans JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors JNK Mitogen-Activated Protein Kinases - physiology Liver Neoplasms - drug therapy Liver Neoplasms - genetics Mice Mice, Knockout Mice, Transgenic Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism TNF-Related Apoptosis-Inducing Ligand - therapeutic use
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Summary:	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. 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. 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. 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.
ISSN:	1468-3288
DOI:	10.1136/gut.2008.154625