Specific resistance upon lentiviral TRAIL transfer by intracellular retention of TRAIL receptors

Tobias Longin Haas, T. Wenger, J. Mattern, R. Penzel, N. Gassler, M. R. Sprick, H. Walczak, P. H. Krammer, K. M. Debatin, I. Herr

Risultato della ricerca: Contributo in rivistaArticolo in rivista

18 Citazioni (Scopus)

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. © 2006 Nature Publishing Group. All rights reserved.
Lingua originaleEnglish
pagine (da-a)1740-1751
Numero di pagine12
RivistaCell Death and Differentiation
Volume13
DOI
Stato di pubblicazionePubblicato - 2006

Keywords

  • Cancer therapy
  • Cell Biology
  • Gene therapy
  • Lentiviral vector
  • Resistance mechanism
  • TRAIL

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