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
| Autor: | J L, Kenney, M E, Guinness, M, Reiss, J, Lacy |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
B-Lymphocytes
Antineoplastic Agents Hormonal Lymphoma Immunoblotting Down-Regulation Apoptosis Cell Separation Flow Cytometry Antineoplastic Agents Phytogenic DNA Antisense Dexamethasone Neoplasm Proteins Viral Matrix Proteins Proto-Oncogene Proteins c-bcl-2 Transforming Growth Factor beta Vincristine Cyclins Tumor Cells Cultured Cyclin D2 Humans Myeloid Cell Leukemia Sequence 1 Protein Cell Division Cell Line Transformed Etoposide |
| Zdroj: | International journal of cancer. 91(1) |
| ISSN: | 0020-7136 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text