Specific resistance upon lentiviral TRAIL transfer by intracellular retention of TRAIL receptors.
Cell Death Differ
; 13(10): 1740-51, 2006 Oct.
Article
em En
| MEDLINE
| ID: mdl-16470224
ABSTRACT
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in many transformed cells, suggesting TRAIL as an ideal candidate for cancer gene therapy. A main obstacle in cancer therapy is intrinsic or acquired therapy resistance of malignant cells. To study induction of resistance against TRAIL, we generated lentiviral vectors allowing efficient TRAIL expression and apoptosis induction in a variety of human cancer cell lines. Within days upon TRAIL overexpression, cells became resistant towards TRAIL, but not to CD95 ligation or DNA damage by cisplatin. Cell surface expression of TRAIL receptors 1 and 2 was completely abrogated in resistant cells due to intracellular retention of the receptors by TRAIL. SiRNA directed against TRAIL resensitized the resistant cells by restoring cell surface expression of TRAIL receptors. These findings represent a novel resistance mechanism towards TRAIL, specifically caused by TRAIL overexpression, and question the use of TRAIL expression in tumor-cell targeting gene therapy.
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Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
/
Fator de Necrose Tumoral alfa
/
Receptores do Fator de Necrose Tumoral
/
Lentivirus
/
Proteínas Reguladoras de Apoptose
Idioma:
En
Ano de publicação:
2006
Tipo de documento:
Article