title: Epstein-Barr virus latent membrane protein-1 protects B-cell lymphoma from rituximab-induced apoptosis through miR-155-mediated Akt activation and up-regulation of Mcl-1.
abstract: Rituximab is a CD20-targeted monoclonal antibody widely used in the treatment of B-cell lymphoma. Previously, we have shown that Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) increases chemoresistance in malignant cancer cells. In this study we examined the effects of LMP1 on the response of B-cell lymphoma cell lines to rituximab. Here we show for the first time that LMP1 activates the Akt pathway and up-regulates Mcl-1 through miR-155 expression, which contributes to the survival of rituximab-treated B-cell lymphoma cells. Furthermore, Akt inhibition or knockdown of Mcl-1 and miR-155 was found to be an efficient strategy to overcome rituximab resistance caused by LMP1 expression. Thus, we propose Akt and Mcl-1 and miR-155 as molecular targets for therapeutic intervention in the treatment of EBV-associated B-cell lymphoma with rituximab.
authors.affiliation: Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Joo Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Won Seog
authors.initials: WS
authors.lastname: Kim
authors.forename: Chaehwa
authors.initials: C
authors.lastname: Park
mesh_terms: D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D000069283:Rituximab; D014763:Viral Matrix Proteins / Q000378:metabolism*
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D014763:Viral Matrix Proteins; D000069283:Rituximab