title: Troglitazone-mediated sensitization to TRAIL-induced apoptosis is regulated by proteasome-dependent degradation of FLIP and ERK1/2-dependent phosphorylation of BAD.
abstract: Resistance to apoptosis is one reason for the poor response of malignant brain tumors to therapy. The PPARgamma-modulating drug Troglitazone downregulates 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 downregulated 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 PPARgamma 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.affiliation: Molecular Neuro-Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Grund
authors.forename: Rezvan
authors.initials: R
authors.lastname: Ahmadi
authors.forename: Fortunata
authors.initials: F
authors.lastname: Jung
authors.forename: Verena
authors.initials: V
authors.lastname: Funke
authors.forename: Georg
authors.initials: G
authors.lastname: Gdynia
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Jaromir
authors.initials: J
authors.lastname: Sykora
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: Stefan
authors.initials: S
authors.lastname: Joos
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Otmar D
authors.initials: OD
authors.lastname: Wiestler
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology / Q000627:therapeutic use*; D005910:Glioma / Q000473:pathology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D000077288:Troglitazone; D051025:bcl-Associated Death Protein / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C494819:BAD protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002839:Chromans; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D045162:Thiazolidinediones; D051025:bcl-Associated Death Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D046988:Proteasome Endopeptidase Complex; D000077288:Troglitazone