Adenovirus-mediated transfer of caspase-8 augments cell death in gliomas: implication for gene therapy.
Caspase-8 is a member of the family of caspases, which are involved in the execution of apoptosis. To investigate whether caspase-8 can be used for gene therapy of gliomas, we transduced A-172 and U251 glioma cells with the caspase-8 gene via an adenoviral vector (Adv) controlled by the chicken beta-actin (CA) promoter (Advcaspase-8), and found that a similar level of caspase-8 protein induced A-172 cells to undergo necrotic cell death and U251 cells to undergo apoptotic cell death. Neither Bcl-XL nor Bcl-2, which play important roles in antiapoptotic mechanisms in gliomas, protected glioma cells from apoptosis induced by overexpression of caspase-8. Injection of Adv-caspase-8 suppressed the in vivo growth of U251 xenografts, in which apoptotic cell death remarkably increased as revealed by TUNEL analysis. Finally, we assessed whether gene therapy with a tissue-specific promoter, the myelin basic protein (MBP) promoter, is applicable to gliomas. Adv for caspase-8 controlled by the MBP promoter induced drastic apoptosis in U251 and U-373MG glioma cells, whereas it did not induce apoptosis in human endothelial cells, fibroblasts, and nerve growth factor-treated PC12 cells. These results indicate that Adv for caspase-8 effectively induced cell death in gliomas, and that this approach may be a useful modality for gene therapy of gliomas.
Shinoura
N
N
Department of Molecular Biotherapy Research, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Koike
H
H
Furitu
T
T
Hashimoto
M
M
Asai
A
A
Kirino
T
T
Hamada
H
H
D000199:Actins / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000628:therapy*; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics*; D002469:Cell Separation; D053938:DNA Fragmentation; D004171:Diploidy; D004727:Endothelium / Q000166:cytology; D005347:Fibroblasts / Q000473:pathology; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000628:therapy*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008854:Microscopy, Electron; D004676:Myelin Basic Protein / Q000235:genetics; D009336:Necrosis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy; D020932:Nerve Growth Factor / Q000494:pharmacology; D016716:PC12 Cells; D011401:Promoter Regions, Genetic; D051381:Rats; D014161:Transduction, Genetic
D000199:Actins; D004676:Myelin Basic Protein; D020932:Nerve Growth Factor; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases