title: Sodium arsenite induces apoptosis and Epstein-Barr virus reactivation in lymphoblastoid cells.
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.
authors.affiliation: LBCM, FSB, Université des Sciences et de la Technologie Houari Boumediene (USTHB), BP 32, El Alia, Bab Ezzouar, 16111 Algiers, Algeria; INSERM UMR-S 1124, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France.
authors.forename: Abderezak
authors.initials: A
authors.lastname: Zebboudj
authors.affiliation: INSERM UMR-S 1124, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France.
authors.forename: Mohamed Ali
authors.initials: MA
authors.lastname: Maroui
authors.affiliation: INSERM UMR-S 1124, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Dutrieux
authors.affiliation: LBCM, FSB, Université des Sciences et de la Technologie Houari Boumediene (USTHB), BP 32, El Alia, Bab Ezzouar, 16111 Algiers, Algeria.
authors.forename: Chafia
authors.initials: C
authors.lastname: Touil-Boukoffa
authors.affiliation: LBCM, FSB, Université des Sciences et de la Technologie Houari Boumediene (USTHB), BP 32, El Alia, Bab Ezzouar, 16111 Algiers, Algeria.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Bourouba
authors.affiliation: INSERM UMR-S 1124, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France.
authors.forename: Mounira K
authors.initials: MK
authors.lastname: Chelbi-Alix
authors.affiliation: INSERM UMR-S 1124, Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France. Electronic address: sebastien.nisole@inserm.fr.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Nisole
mesh_terms: D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D018053:Arsenites / Q000494:pharmacology*; D001324:Autoantigens / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology; D000071156:Promyelocytic Leukemia Protein; D017670:Sodium Compounds / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism
chemical_list: D034961:Antigens, Nuclear; D001152:Arsenicals; D018053:Arsenites; D001324:Autoantigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D017670:Sodium Compounds; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014763:Viral Matrix Proteins; C066642:SP100 protein, human; C070576:PML protein, human; C017947:sodium arsenite; D000077237:Arsenic Trioxide
keywords: Arsenic; Epstein–Barr virus; LMP1; Latency; PML