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Antisense to the Epstein‐Barr virus (EBV)‐encoded latent membrane protein 1 (LMP‐1) sensitizes EBV‐immortalized B cells to transforming growth factor‐beta and chemotherapeutic agents
Author(s) -
Kenney Jamie L.,
Guinness Mary E.,
Reiss Michael,
Lacy Jill
Publication year - 2000
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(20010101)91:1<89::aid-ijc1015>3.0.co;2-u
Subject(s) - biology , etoposide , epstein–barr virus , cancer research , apoptosis , antisense rna , cell growth , cell culture , microbiology and biotechnology , virus , virology , gene expression , chemotherapy , biochemistry , gene , genetics
The Epstein‐Barr virus (EBV)‐encoded latent membrane protein 1 (LMP‐1) is absolutely required for EBV transformation of B cells. LMP‐1 mimics a constitutively activated receptor of the tumor necrosis factor receptor family, mediating diverse oncogenic functions that influence growth, differentiation and susceptibility to apoptosis. Given the critical functions of LMP‐1 in EBV‐associated transformation, it represents a rational therapeutic target for modulation. We used antisense oligodeoxynucleotides targeted to LMP‐1 as a strategy to suppress LMP‐1 expression and thereby inhibit its functions. In previous studies, we have shown that short‐term treatment of EBV‐positive lymphoblastoid cell lines (LCLs) with LMP‐1 antisense oligodeoxynucleotides can dramatically reduce levels of LMP‐1 protein in association with inhibition of proliferation, stimulation of apoptosis, down‐regulation of Bcl‐2 and Mcl‐1 and enhanced sensitivity to the chemotherapeutic agent, etoposide. Here, we provide further evidence of the profound effects of reducing LMP‐1 levels using antisense oligodeoxynucleotides in EBV‐transformed B cells. We have shown that LMP‐1 antisense treatment of LCLs partially restores sensitivity to the anti‐proliferative and apoptotic effects of transforming growth factor‐beta, a potent negative regulator of normal human B‐cell growth, in association with a reduction in cyclin D2 levels. In addition, LMP‐1 antisense sensitizes LCLs to chemotherapeutic drugs from diverse classes, including etoposide, vincristine and dexamethasone, by enhancing apoptotic cell death. Finally, the anti‐proliferative and apoptotic effects of LMP‐1 antisense treatment were observed not only in laboratory‐derived LCLs, but also in an EBV‐positive cell line derived from an AIDS‐related lymphoma. These studies demonstrate that antisense targeting of LMP‐1 represents a rational therapeutic strategy for EBV‐positive lymphoproliferative disorders. Int. J. Cancer 91:89–98, 2001. © 2001 Wiley‐Liss, Inc.