title: Resistance to fludarabine-induced apoptosis in Epstein-Barr virus infected B cells.
abstract: The Epstein-Barr virus (EBV) transforms B cells in part by inhibiting the cellular apoptotic programme. This is also observed when Burkitt lymphoma cell lines are infected with EBV. Induction of apoptosis is one of the mechanisms by which fludarabine inhibits the growth of cells with low proliferative capacity. This compound can also inhibit several other mechanisms in the cell, including inhibition of the synthesis of factors such as STAT1. To analyse the relationship between EBV status, fludarabine-induced apoptosis, and transcription factors we studied the EBV-negative Burkitt lymphoma cell line BL2, its EBV-infected counterpart BL2.B95.8 and the EBV-transformed cell line PRI. The BL2 cell line was found to be very sensitive to fludarabine. The BL2.B95.8 and PRI cells were both resistant but the latter to a lesser extent. In the PRI cells fludarabine activated p53, but not in the BL2.B95.8 cells in which the p53 pathway is inactivated. We observed that this inactivation results in part from the lack of expression of the MDM2 inhibitor p14ARF. Conversely, there was a substantial constitutive activation of STAT1, and not of the other STATs, in the BL2.B95.8 cells and a modest one in the PRI cells. Furthermore, expression of STAT1 was significantly reduced by fludarabine treatment in the PRI cells, but not in the BL2.BL95.8 cells. Finally, the expression of p21WAF1/CIP1 was detected only in the BL2.B95.8 and PRI cells. This protein, known to play a role in cell survival, may therefore be involved in the resistance of the BL2.B95.8 cells to fludarabine.
authors.affiliation: EA 3406 (ATHSCO), Université Paris 13 UFR SMBH Bobigny cedex, France. remi.fagard@avc.ap-hop-paris.fr
authors.forename: Remi
authors.initials: R
authors.lastname: Fagard
authors.forename: Houria
authors.initials: H
authors.lastname: Mouas
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dusanter-Fourt
authors.forename: Christine
authors.initials: C
authors.lastname: Devillers
authors.forename: Philippe
authors.initials: P
authors.lastname: Bissières
authors.forename: Antoine
authors.initials: A
authors.lastname: Martin
authors.forename: Gilbert
authors.initials: G
authors.lastname: Lenoir
authors.forename: Huynh
authors.initials: H
authors.lastname: VanTan
authors.forename: Jean
authors.initials: J
authors.lastname: Feuillard
authors.forename: Martine
authors.initials: M
authors.lastname: Raphaël
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000473:pathology / Q000821:virology*; D015153:Blotting, Western; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D004247:DNA; D014740:Vidarabine; C024352:fludarabine