Troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via down-regulation of FLIP and Survivin.
Induction of apoptosis by the death ligand TRAIL might be a promising therapeutic approach in cancer therapy. However, since not all tumor cells are sensitive to TRAIL, there is a need for the development of strategies to overcome TRAIL-resistance. The results of the present study show that the anti-diabetic drug troglitazone sensitizes human glioma and neuroblastoma cells to TRAIL-induced apoptosis. This process is accompanied by a substantial increase of active caspase 8 and active caspase 3, but it is independent of troglitazone's effects on the nuclear receptor PPAR-gamma. Troglitazone induces a pronounced reduction in protein expression levels of the anti-apoptotic FLICE-inhibitory protein (FLIP) without affecting FLIP mRNA levels. Further, protein and mRNA expression levels of the anti-apoptotic protein Survivin significantly decrease upon treatment with troglitazone. Moreover, sensitization to TRAIL is partly accompanied by an up-regulation of the TRAIL receptor, TRAIL-R2. A combined treatment with troglitazone and TRAIL might be a promising experimental therapy because troglitazone sensitizes tumor cells to TRAIL-induced apoptosis via various mechanisms, thereby minimizing the risk of acquired tumor cell resistance.
Schultze
Kerstin
K
Molecular Neuro-Oncology, German Cancer Research Center, DKFZ, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
Böck
Barbara
B
Eckert
Anika
A
Oevermann
Lena
L
Ramacher
Dirk
D
Wiestler
Otmar
O
Roth
Wilfried
W
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation; D004357:Drug Synergism; D005909:Glioblastoma / Q000188:drug therapy; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy; D047495:PPAR gamma / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002839:Chromans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D047495:PPAR gamma; D018124:Receptors, Tumor Necrosis Factor; D000077022:Survivin; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D045162:Thiazolidinediones; D020169:Caspases; D000077288:Troglitazone