Adenoviral (full-length) Apo2L/TRAIL gene transfer is an ineffective treatment strategy for malignant glioma.
Death ligand-mediated apoptosis is a promising strategy of gene therapy for human malignant glioma. We here report that the infection of human malignant glioma cell lines with an adenoviral vector encoding full length human Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Ad-Apo2L/TRAIL) results in strong Apo2L/TRAIL transgene expression and the release of full-length Apo2L/TRAIL into the cell culture medium. However, Ad-Apo2L/TRAIL is a poor inducer of cell death, even in the presence of inhibitors of protein synthesis, in human glioma cell lines which are sensitive to soluble recombinant human His-tagged Apo2L/TRAIL (amino acids 114-281). Moreover, Ad-Apo2L/TRAIL gene transfer inhibits soluble His-tagged Apo2L/TRAIL-induced apoptosis, strongly suggesting that the adenovirally encoded full-length Apo2L/TRAIL is not a suitable molecule for glioma cancer gene therapy. This study has important implications for the future development of therapeutic strategies aiming at death receptor activation in refractory cancers such as malignant glioma.
Naumann
Ulrike
U
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Hoppe-Seyler-Str 3, D-72076 Tübingen, Germany. ulrike.naumann@uni-tuebingen.de
Waltereit
Robert
R
Schulz
Jörg B
JB
Weller
Michael
M
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D061945:Caspase Inhibitors; D002455:Cell Division; D003513:Cycloheximide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D049452:Green Fluorescent Proteins; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D008164:Luminescent Proteins / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D008024:Ligands; D008164:Luminescent Proteins; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505655:Tnfsf10 protein, rat; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D003513:Cycloheximide