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.

Download full-text


Available from: Eike Gallmeier, Apr 09, 2015
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The c-Jun NH2-terminal kinases (JNKs) are master protein kinases that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. It is increasingly apparent that persistent activation of JNKs are involved in cancer development and progression. Therefore, JNKs represent attractive targets for therapeutic intervention with small molecule kinase inhibitors. However, evidence supportive of a tumor suppressor role for the JNK proteins has also been documented. Recent studies showed that the two major JNK proteins, JNK1 and JNK2, have distinct or even opposing functions in different types of cancer. As such, close consideration of which JNK proteins are beneficial targets and more importantly what effect small molecule inhibitors of JNKs have on physiological processes are an absolute must. A number of ATP-competitive and ATP-noncompetitive JNK inhibitors have been developed, but have several limitations such as a lack of specificity and cellular toxicity. In this review we summarize the accumulating evidence supporting a role for the JNK proteins in the pathogenesis of different solid and hematological malignancies and discuss many challenges and scientific opportunities in the targeting of JNKs in cancer.
    British Journal of Pharmacology 09/2013; 171(1). DOI:10.1111/bph.12432 · 4.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In general, it is difficult to realize the optimal operation of waste water treatment plant because of its complex nature (e.g., highly nonlinear, seriously coupled, higher order, time-varying and frequent variation of operating condition). An integrated automation system consisting of two layers: process manage system (PMS) and process control system (PCS), is developed to overcome the problem of high production costs in wastewater treatment plants in China because of low automation level. The structure, function and control strategy of the system are discussed. The system proposed in this paper has been successfully applied to the wastewater treatment plant in the southern suburb of Shenyang, realizing the optimal control of overall production index including wastewater treatment yield, treated wastewater quality and production cost. It has been found to provide great benefits for both economy and society.
    Machine Learning and Cybernetics, 2005. Proceedings of 2005 International Conference on; 09/2005
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: TRAIL induced apoptosis of tumor cells is currently entering phase II clinical settings, despite the fact that not all tumor types are sensitive to TRAIL. TRAIL resistance in ovarian carcinomas can be caused by a blockade upstream of the caspase 3 signaling cascade. We explored the ability of restriction endonucleases to directly digest DNA in vivo, thereby circumventing the caspase cascade. For this purpose, we delivered enzymatically active endonucleases via the cationic amphiphilic lipid SAINT-18((R)):DOPE to both TRAIL-sensitive and insensitive ovarian carcinoma cells (OVCAR and SKOV-3, respectively). Functional nuclear localization after delivery of various endonucleases (BfiI, PvuII and NucA) was indicated by confocal microscopy and genomic cleavage analysis. For PvuII, analysis of mitochondrial damage demonstrated extensive apoptosis both in SKOV-3 and OVCAR. This study clearly demonstrates that cellular delivery of restriction endonucleases holds promise to serve as a novel therapeutic tool for the treatment of resistant ovarian carcinomas.
    Experimental Cell Research 07/2009; 315(15):2487-95. DOI:10.1016/j.yexcr.2009.06.011 · 3.25 Impact Factor
Show more