Caspase-8 gene transduction augments radiation-induced apoptosis in DLD-1 cells.
Caspase-8 is a member of the cysteine protease family that plays a critical role in death receptor-mediated apoptosis. We previously demonstrated that adenovirally transduced caspase-8 efficiently induced apoptosis in tumor cells (Shinoura et al. (2000) Hum. Gene Ther. 11, 1123-1137). However, to ensure safety in clinical applications some devise for minimization of the dose of adenoviral vector required for sufficient antitumor effect is needed. In this study, we evaluated the proapoptotic effect in DLD-1 colon cancer cells of a combination of low-dose infection with an adenoviral vector expressing caspase-8 and X-ray irradiation. Under these conditions, X-ray irradiation strongly induced apoptosis whereas irradiation without transduction only had a trace proapoptotic effect. Overexpression of bcl-xL strongly blocked the activation of caspase-8 and induction of apoptosis, suggesting that adenovirally transduced caspase-8 was activated at a point downstream of mitochondria. This combination strategy may be a useful modality for gene therapy of colorectal cancer.
Uchida
Hiroaki
H
Department of Molecular Medicine, Sapporo Medical University, S1 W17 Chuo-ku, Sapporo 060-8556, Japan.
Shinoura
Nobusada
N
Kitayama
Joji
J
Watanabe
Toshiaki
T
Nagawa
Hirokazu
H
Hamada
Hirofumi
H
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000528:radiation effects; D008954:Models, Biological; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases