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

• Published in: International journal of cancer 2001-01, Vol.91 (1), p.89-98
• Main Authors: Kenney, Jamie L., Guinness, Mary E., Reiss, Michael, Lacy, Jill
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents, Hormonal - pharmacology; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; B-Lymphocytes - metabolism; Biological and medical sciences; Cell Division - drug effects; Cell Line, Transformed; Cell Separation; CMP‐1; Cyclin D2; Cyclins - metabolism; Dexamethasone - pharmacology; DNA, Antisense - metabolism; DNA, Antisense - therapeutic use; Down-Regulation; Epstein-Barr virus; Etoposide - pharmacology; Flow Cytometry; General aspects; Humans; Immunoblotting; latent membrane protein 1; Lymphoma - metabolism; Medical sciences; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins - metabolism; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-bcl-2 - metabolism; Transforming Growth Factor beta - metabolism; Tumor Cells, Cultured; Vincristine - pharmacology; Viral Matrix Proteins - genetics
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/1097-0215(20010101)91:1<89::AID-IJC1015>3.0.CO;2-U

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.