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

University of Munich, University Hospital Grosshadern, Department of Medicine II, Research Lab B 5 E01 308, Marchioninistrasse 15, D-81377 Munich, Germany.
Gut (Impact Factor: 14.66). 05/2009; 58(5):688-98. DOI: 10.1136/gut.2008.154625
Source: PubMed


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.

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Available from: Eike Gallmeier, Apr 09, 2015
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    • "Additionally, inhibition of JNK activity has been shown to improve the efficacy of some current chemotherapeutic agents. For example, SP600125, in combination with the chemotherapy drug TNF-related apoptosis-inducing ligand, was shown to increase apoptosis in human HCC cultures (Mucha et al., 2009). Indeed, activated JNK1 was found in tissue samples from patients with HCC (Hui et al., 2008), and correlates directly with poor therapeutic response to sorafenib, a multikinase inhibitor that is currently being tested in clinical trials for HCC (Hagiwara et al., 2012). "
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