Article Text

other Versions

PDF
JNK inhibition sensitizes hepatocellular carcinoma cells but not normal hepatocytes to TNF-related apoptosis inducing ligand
  1. Simon R Mucha
  1. University of Munich - Dept. of Clinical Medicine 2, Germany
    1. Antonia Rizzani
    1. University of Munich - Dept. of Clinical Medicine 2, Germany
      1. Alexander Gerbes
      1. University of Munich - Dept. of Clinical Medicine 2, Germany
        1. Peter Camaj
        1. University of Munich - Dept. of Sugery, Germany
          1. Wolfgang Thasler
          1. University of Munich - Dept. of Sugery, Germany
            1. Christiane Bruns
            1. University of Munich - Dept. of Sugery, Germany
              1. Sören Eichhorst
              1. University of Munich - Dept. of Clinical Medicine 2, Germany
                1. Eike Gallmeier
                1. University of Munich - Dept. of Clinical Medicine 2, Germany
                  1. Frank Kolligs
                  1. University of Munich - Dept. of Clinical Medicine 2, Germany
                    1. Burkhard Göke
                    1. University of Munich - Dept. of Clinical Medicine 2, Germany
                      1. Enrico N De Toni (enrico.detoni{at}med.uni-muenchen.de)
                      1. University of Munich - Dept. of Clinical Medicine 2, Germany

                        Abstract

                        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.

                        Statistics from Altmetric.com

                        Request permissions

                        If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.