Abstract |
Epstein-Barr virus (EBV) is associated with several malignancies, including carcinomas, such as nasopharyngeal carcinoma, and lymphomas, such as Burkitt's lymphoma and Hodgkin's lymphoma. The Latent Membrane Protein 1 (LMP1) is the major oncogene protein of EBV as its expression is responsible for the induction of cell transformation, immortalization and proliferation. Arsenic trioxide was shown to induce a cytotoxic effect on nasopharyngeal cancer cells associated with LMP1 down-regulation. However, the effect of arsenic on EBV-associated lymphoproliferative malignancies has been less studied. We investigated the effect of two different arsenical compounds, arsenic trioxide ( As2O3) and sodium arsenite (NaAsO2) on the induction of cell death in P3HR1 cells, an Epstein-Barr virus-positive Burkitt lymphoma derived cell line. Both compounds inhibited cell growth and induced cell death. By flow-cytometry and Western blot analysis, we provide evidence that NaAsO2 induced caspase-dependent apoptosis whereas As2O3 triggered autophagic cell death. Furthermore, we show that NaAsO2 treatment led to a dramatic decrease of the expression level of LMP1 and the cellular protein PML. Importantly, this down-regulation was associated with a reactivation of EBV lytic cycle through the induction of immediate-early proteins Zta and Rta. These results are in agreement with a model in which LMP1 maintains EBV in a latent state by stabilizing PML expression. Altogether, our results suggest that NaAsO2 would represent a better therapeutic candidate than As2O3 in EBV-induced B lymphoma for its capacity to promote viral reactivation.
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Authors | Abderezak Zebboudj, Mohamed Ali Maroui, Jacques Dutrieux, Chafia Touil-Boukoffa, Mehdi Bourouba, Mounira K Chelbi-Alix, Sébastien Nisole |
Journal | Biochimie
(Biochimie)
Vol. 107 Pt B
Pg. 247-56
(Dec 2014)
ISSN: 1638-6183 [Electronic] France |
PMID | 25241256
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2014 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved. |
Chemical References |
- Antigens, Nuclear
- Arsenicals
- Arsenites
- Autoantigens
- EBV-associated membrane antigen, Epstein-Barr virus
- Nuclear Proteins
- Oxides
- Promyelocytic Leukemia Protein
- Sodium Compounds
- Transcription Factors
- Tumor Suppressor Proteins
- Viral Matrix Proteins
- SP100 protein, human
- PML protein, human
- sodium arsenite
- Arsenic Trioxide
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Topics |
- Antigens, Nuclear
(metabolism)
- Apoptosis
(drug effects)
- Arsenic Trioxide
- Arsenicals
(pharmacology)
- Arsenites
(pharmacology)
- Autoantigens
(metabolism)
- Autophagy
(drug effects)
- Burkitt Lymphoma
(pathology, virology)
- Cell Line, Tumor
(drug effects)
- Cell Proliferation
(drug effects)
- Herpesvirus 4, Human
(drug effects, metabolism)
- Humans
- Nuclear Proteins
(metabolism)
- Oxides
(pharmacology)
- Promyelocytic Leukemia Protein
- Sodium Compounds
(pharmacology)
- Transcription Factors
(metabolism)
- Tumor Suppressor Proteins
(metabolism)
- Viral Matrix Proteins
(metabolism)
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