title: Constitutive autophagy contributes to resistance to TP53-mediated apoptosis in Epstein-Barr virus-positive latency III B-cell lymphoproliferations.
abstract: The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders and lymphomas. We have previously demonstrated that treating wild-type TP53-expressing B cell lines with the TP53 pathway activator nutlin-3 induced apoptosis in EBV-negative and EBV-positive latency I cells whereas EBV-positive latency III cells remained much more apoptosis-resistant. Here, we report a constitutively high level of autophagy in these resistant cells which express high levels of the proautophagic protein BECN1/Beclin 1 based, at least in part, on the activation of the NFKB signaling pathway by the viral protein LMP1. Following treatment with nutlin-3, several autophagy-stimulating genes were upregulated both in EBV-negative and EBV-positive latency III cells. However the process of autophagy was only triggered in the latter and was associated with an upregulation of SESN1/sestrin 1 and inhibition of MTOR more rapid than in EBV-negative cells. A treatment with chloroquine, an inhibitor of autophagy, potentiated the apoptotic effect of nutlin-3, particularly in those EBV-positive cells which were resistant to apoptosis induced by nutlin-3 alone, thereby showing that autophagy participates in this resistant phenotype. Finally, using immunohistochemical staining, clinical samples from various B cell lymphoproliferations with the EBV-positive latency II or III phenotype were found to harbor a constitutively active autophagy.
authors.affiliation: a UMR 8126 CNRS; Univ Paris-Sud; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Pujals
authors.affiliation: a UMR 8126 CNRS; Univ Paris-Sud; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Loëtitia
authors.initials: L
authors.lastname: Favre
authors.affiliation: a UMR 8126 CNRS; Univ Paris-Sud; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pioche-Durieu
authors.affiliation: a UMR 8126 CNRS; Univ Paris-Sud; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Aude
authors.initials: A
authors.lastname: Robert
authors.affiliation: b Functional Genomic Platform; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Meurice
authors.affiliation: b Functional Genomic Platform; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Marion
authors.initials: M
authors.lastname: Le Gentil
authors.affiliation: a UMR 8126 CNRS; Univ Paris-Sud; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Chelouah
authors.affiliation: c CHU Henri Mondor; Assistance Publique-Hôpitaux de Paris; Département de Pathologie; Inserm U955; Université Paris-Est Créteil ; Créteil , France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Martin-Garcia
authors.affiliation: a UMR 8126 CNRS; Univ Paris-Sud; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Eric
authors.initials: E
authors.lastname: Le Cam
authors.affiliation: d Service d'Anatomie Pathologique; Hôpital Bicêtre; Le Kremlin-Bicêtre ; Le Kremlin-Bicêtre , France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Guettier
authors.affiliation: a UMR 8126 CNRS; Univ Paris-Sud; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Martine
authors.initials: M
authors.lastname: Raphaël
authors.affiliation: e Roche Research Center; Hoffmann-La Roche Inc. ; Nutley , NJ USA.
authors.forename: Lyubomir T
authors.initials: LT
authors.lastname: Vassilev
authors.affiliation: c CHU Henri Mondor; Assistance Publique-Hôpitaux de Paris; Département de Pathologie; Inserm U955; Université Paris-Est Créteil ; Créteil , France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Gaulard
authors.affiliation: f INSERM U845; Necker Growth and Signaling Research Center; University Paris Descartes ; Paris , France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Codogno
authors.affiliation: a UMR 8126 CNRS; Univ Paris-Sud; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lipinski
authors.affiliation: a UMR 8126 CNRS; Univ Paris-Sud; Institut Gustave Roussy ; Villejuif , France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Wiels
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology* / Q000821:virology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D004854:Herpesvirus 4, Human; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008223:Lymphoma / Q000473:pathology* / Q000821:virology; D010879:Piperazines / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D007093:Imidazoles; D010879:Piperazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3
keywords: BECN1; Burkitt lymphoma; EBV; TP53; autophagy; nulin-3