Abstract
Resveratrol (3,4',5-trihydroxy-trans-stilbene), a polyphenolic natural product, shows chemopreventive properties against several cancers, heart diseases, inflammation, and viral infections. Epstein Barr virus (EBV), a γ-herpesvirus, contributes to the development of several human cancers including Burkitt's lymphoma (BL). In this study, we asked whether treatment with resveratrol would affect the viability of EBV-positive BL cells displaying different forms of latency. We report here that resveratrol, regardless of EBV status, induces caspase-dependent apoptosis by arresting cell-cycle progression in G(1) phase. However, resveratrol strongly induced apoptosis in EBV(-) and latency I EBV(+) cells, whereas latency II and latency III EBV(+) BL cells showed a survival advantage that increased with the extent of the pattern of viral gene expression. Resveratrol-induced cell-cycle arrest and apoptosis occurred in association with induction of p38 MAPK phosphorylation and suppression of ERK1/2 signaling pathway. Moreover, NF-κB DNA-binding activity was inhibited in all BL lines except EBV(+) latency III cells. LMP1 oncogene, which is expressed in latency III phenotype, is involved with the higher resistance to the antiproliferative effect of resveratrol because siRNA-mediated inhibition of LMP1 greatly increased the sensitivity of latency III BL cells as well as that of lymphoblastoid cell lines to the polyphenol. We propose that a combined resveratrol/siRNA strategy may be a novel approach for the treatment of EBV-associated B-cell malignancies in which the viral pattern of gene expression has been defined.
Highlights
Epstein Barr virus (EBV), the causative agent of infectious mononucleosis, is associated with a variety of different human tumors including Burkitt's lymphoma (BL), nasopharyngeal carcinoma, Hodgkin's disease, and posttransplant lymphoproliferative disorders occurring in immunocompromised patients
As we aimed to determine whether EBV gene expression played a role on the susceptibility of BL cells to resveratrol, we tested 2 EBV(À) BL cell lines (2A8 and Ramos) and 3 EBV(þ) BL cell lines, the latter expressing different patterns of EBV latency genes
The experiments carried out in 3 EBV-positive BL lines that express just EBNA1 as in Akata, a latency II-like pattern with the exception of LMP1 (EBNA1þ/LMP2Aþ) as in Jijoye M13, and the latency III phenotype as in Raji, respectively, have allowed us to evaluate the antiproliferative effect of resveratrol on cells in which EBV infection was associated with a specific degree of protection from apoptosis
Summary
Epstein Barr virus (EBV), the causative agent of infectious mononucleosis, is associated with a variety of different human tumors including Burkitt's lymphoma (BL), nasopharyngeal carcinoma, Hodgkin's disease, and posttransplant lymphoproliferative disorders occurring in immunocompromised patients. In all these malignancies, the virus establishes a latent infection characterized by different EBV gene expression profiles. EBNA1 is the only viral antigen expressed in latency I phenotype mainly found in EBV-positive Burkitt's. Authors' Affiliations: Departments of 1Public Health and Infectious Diseases and 2Experimental Medicine, University of Rome "Sapienza", Rome, Italy. Arena: IRCCS Casa Sollievo della Sofferenza, Mendel Laboratory, Rome, Italy
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