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Adenoviral natural born killer gene therapy for malignant glioma

Item Type:Article
Title:Adenoviral natural born killer gene therapy for malignant glioma
Creators Name:Naumann, U. and Schmidt, F. and Wick, W. and Frank, B. and Weit, S. and Gillissen, B. and Daniel, P. and Weller, M.
Abstract:Glioblastoma is a lethal neoplasm resistant to conventional radiotherapy and chemotherapy. Natural born killer (NBK), also known as Bcl-2-interacting killer (BIK), is a death-promoting Bcl-2 family protein sharing with Bcl-2 only the Bcl homology 3 (BH3) domain. We here report that an adenoviral vector encoding NBK (Ad-NBK) uniformly induces cell death in 12 human malignant glioma cell lines. Ad-NBK-induced cell death involves neither quantitative mitochondrial cytochrome c release nor caspase 8, 9, 7, or 3 processing and is unaffected by the viral caspase inhibitor, cytokine response modifier A (CRM-A), or selective caspase 8 or 9 inhibitors. In contrast, Ad-NBK-induced cell death is inhibited by the broad-range caspase inhibitor, zVAD-fmk, or by adenoviral gene transfer of the X-linked inhibitor of apoptosis protein (XIAP). Further, Ad-NBK-induced cell death is inhibited by Bcl-2 or Bcl-xL gene transfer. Interestingly, Bcl-2- and Bcl-xL-transfected glioma cells, which are partially protected from Ad-NBK-induced cell death, accumulate much higher levels of NBK than are ever observed in control-infected cells. This indicates that complex formation with Bcl-2 or Bcl-xL sequesters NBK in an inactive form and that free NBK, rather than an NBK-mediated depletion of free antiapoptotic Bcl-2 family proteins, is the proximate mediator of Ad-NBK-induced cell death. Conversely, proteasome inhibition-mediated accumulation of NBK strongly enhances Ad-NBK-induced cell death. Finally, Ad-NBK-infected LN-229 glioma cells are not tumorigenic in nude mice. Thus Ad-NBK triggers an XIAP- and zVAD-fmk-sensitive cell death pathway in glioma cells with potential therapeutic value, provided that NBK expression can be selectively targeted to cancer cells.
Keywords:Adenoviridae, Amino Acid Chloromethyl Ketones, Apoptosis, Apoptosis Regulatory Proteins, bcl-2 Genes, Caspase Inhibitors, Fluorometry, Gene Expression, Genetic Therapy, Genetic Vectors, Glioblastoma, Membrane Proteins, Northern Blotting, Nude Mice, Precipitin Tests, Proteins, Tumor Cell Line, X-Linked Inhibitor of Apoptosis Protein, Animals, Mice
Source:Human Gene Therapy
ISSN:1043-0342
Publisher:Mary Ann Liebert (U.S.A.)
Volume:14
Number:13
Page Range:1235-1246
Date:1 September 2003
Official Publication:https://doi.org/10.1089/104303403767740777
PubMed:View item in PubMed

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