Adenoviral-mediated transfer of the TNF-related apoptosis-inducing ligand/Apo-2 ligand gene induces tumor cell apoptosis.
TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily of cytokines that induces apoptosis in a variety of cancer cells. The results presented in this study demonstrate that introduction of the human TRAIL gene into TRAIL-sensitive tumor cells using an adenoviral vector leads to the rapid production and expression of TRAIL protein, and subsequent death of the tumor cells. Tumor cell death was mediated by an apoptotic mechanism, as evidenced by the activation of caspase-8, cleavage of poly(ADP-ribose) polymerase, binding of annexin V, and inhibition by caspase inhibitor zVAD-fmk. These results define a novel method of using TRAIL as an antitumor therapeutic, and suggest the potential use for an adenovirus-encoding TRAIL as a method of gene therapy for numerous cancer types in vivo.
Griffith
T S
TS
Departments of Urology and Internal Medicine, University of Iowa, Iowa City, IA 52242, USA. GriffithT@mail.medicine.uiowa.edu
Anderson
R D
RD
Davidson
B L
BL
Williams
R D
RD
Ratliff
T L
TL
D000260:Adenoviruses, Human / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms; D020126:Brefeldin A / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D004198:Disease Susceptibility; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology; D008024:Ligands; D008297:Male; D008545:Melanoma; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D011471:Prostatic Neoplasms; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology* / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D007141:Immunoglobulin Fc Fragments; D008024:Ligands; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D020126:Brefeldin A