Antisense to the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) suppresses LMP-1 and Bcl-2 expression and promotes apoptosis in EBV-immortalized B cells

The Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP-1) is required for viral transformation and functions to protect cells from apoptotic cell death, in part, by induction of antiapoptotic genes, including Bcl-2 and A20. We have used antisense oligodeoxynucleotides targeted to LMP-1 as...

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Bibliographic Details
Published in:Blood 1998-09, Vol.92 (5), p.1721-1727
Main Authors: KENNEY, J. L, GUINNESS, M. E, CURIEL, T, LACY, J
Format: Article
Language:English
Subjects:
Antineoplastic agents
Apoptosis - genetics
B-Lymphocytes - cytology
B-Lymphocytes - metabolism
Biological and medical sciences
Cell Line, Transformed
Codon
Etoposide - pharmacology
Fetal Blood - cytology
Gene Expression
Herpesvirus 4, Human - genetics
Immunotherapy
Medical sciences
Myeloid Cell Leukemia Sequence 1 Protein
Neoplasm Proteins - genetics
Oligonucleotides, Antisense - pharmacology
Open Reading Frames
Pharmacology. Drug treatments
Proto-Oncogene Proteins c-bcl-2 - genetics
Viral Matrix Proteins - genetics
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Summary:The Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP-1) is required for viral transformation and functions to protect cells from apoptotic cell death, in part, by induction of antiapoptotic genes, including Bcl-2 and A20. We have used antisense oligodeoxynucleotides targeted to LMP-1 as a strategy to suppress LMP-1 expression and thereby inhibit its functions. We have shown that levels of LMP-1 protein in EBV-positive lymphoblastoid cell lines can be reduced by in vitro treatment with unmodified oligodeoxynucleotides targeted to the first five codons of the LMP-1 open-reading frame. Furthermore, suppression of LMP-1 was associated with molecular and phenotypic effects that included downregulation of the LMP-1-inducible antiapoptotic genes, Bcl-2 and Mcl-1, inhibition of proliferation, stimulation of apoptosis, and enhancement of sensitivity to the chemotherapeutic agent, etoposide. These effects were largely sequence-specific and observed in EBV-positive, but not EBV-negative cell lines. These studies suggest that lowering expression of LMP-1 in EBV-associated malignancy might have therapeutic effects and might synergize with other antitumor agents.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.V92.5.1721