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Research Paper

Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD

Kerstin Grund, Rezvan Ahmadi, Fortunata Jung, Verena Funke, Georg Gdynia, Axel Benner, Jaromir Sykora, Henning Walczak, Stefan Joos, Jörg Felsberg, Guido Reifenberger, Otmar D. Wiestler, Christel Herold-Mende and Wilfried Roth

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Resistance to apoptosis is one reason for the poor response of malignant brain tumors to therapy. The PPARγ-modulating drug Troglitazone down-regulates the anti-apoptotic FLIP protein and sensitizes glioblastoma cells to apoptosis induced by the death ligand TRAIL. To investigate the molecular basis of an experimental combination therapy for malignant gliomas with TRAIL and Troglitazone, we investigated the Troglitazone-induced signaling cascades and the expression of TRAIL receptors and FLIP in malignant gliomas. Troglitazone down-regulated the FLIP protein through accelerated ubiquitin/proteasome-dependent degradation, which might be mediated by a Troglitazone-induced increase in reactive oxygen species. Moreover, Troglitazone induced the phosphorylation of the MAP kinase ERK1/2 as well as of the BAD protein. Inhibition of either PPARγ or MEK1/2 blocked the Troglitazone-mediated phosphorylation of BAD and further increased the synergistic induction of glioma cell death by TRAIL and Troglitazone. Immunohistochemical analysis demonstrated that FLIP and TRAIL-R2 were significantly higher expressed in anaplastic (WHO grade III) than in diffuse (WHO grade II) gliomas. High FLIP and low TRAIL-R2 expression levels were associated with a poor prognosis of patients. Our findings warrant a further pre-clinical evaluation of an experimental anti-glioma therapy with TRAIL and Troglitazone, potentially in conjunction with a MAP kinase inhibitor.

Authors

Kerstin Grund

Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

Rezvan Ahmadi

Division of Neurosurgical Research, Department of Neurosurgery; Heidelberg, Germany

Fortunata Jung

Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

Verena Funke

Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

Georg Gdynia

Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

Axel Benner

Division Biostatistics, German Cancer Research Center, Heidelberg, Germany

Jaromir Sykora

Apoptosis Regulation; German Cancer Research Center, Heidelberg, Germany

Henning Walczak

Apoptosis Regulation; German Cancer Research Center, Heidelberg, Germany

Stefan Joos

Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany

Jörg Felsberg

Department of Neuropathology, Heinrich-Heine-University, Duesseldorf, Germany

Guido Reifenberger

Department of Neuropathology, Heinrich-Heine-University, Duesseldorf, Germany

Otmar D. Wiestler

Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

Christel Herold-Mende

Division of Neurosurgical Research, Department of Neurosurgery; Heidelberg, Germany

Wilfried Roth

Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, University of Heidelberg, Germany

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If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.