Translocated in most lymphomas. C-Myc not only regulates cell biological function
Translocated in most lymphomas. C-Myc not only regulates cell biological function but is also involved with sumoylation regulators, such as SUMO2/3 and E1/2/3 ligases [79], which are in turn regulated by arsenic and contribute to degradation of EBV lytic gene expression in lymphoma cells. In contrast, NPC-KT cells are EBV latency type II cells that express the EBV latent genes LMP2A and LMP1, which can PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/25432023 interact with the ubiquitin/proteasome system to regulate gene expression [80, 81]. These interactions could interfere with arsenic’s modulation of the ubiquitin pathway and curb arsenic’s effects on EBV lytic gene expression. Our results show that ATO not only blocks EBV spontaneous reactivation but also reagent-induced reactivation (Fig. 5e), implying that ATO-inhibited EBV lytic gene expression occurs through a broadly utilized pathway. Proteasome or sumoylation inhibitors rescue the ATO-mediated reduction of EBV reactivation in a dose dependent manner. Furthermore, the co-immunoprecipitation experiment reveals that ATO leads to greater (Z)-4-Hydroxytamoxifen dose ubiquitinization of the Zta protein. Thus, these results indicate that ATO induces EBV lytic protein ubiquitination and proteasome-mediated degradation, and that sumoylation may facilitate the degradation process. On the basis of our observations, we propose the molecular mechanistic model for arsenic-mediatedFig. 6 A depiction of how ATO regulates the EBV lytic cycle and cell fate in EBV-positive lymphoma cells. Exposure to ATO induces EBV lytic protein degradation through sumoylation and ubiquitination. Consequent to their degradation, EBV lytic genes cannot activate EBV lytic replication, which in turn diminishes signaling required for cell growth. Ultimately ATO leads to cell death in EBV-positive cellsYin et al. Virology Journal (2017) 14:Page 10 ofdegradation of EBV lytic genes and cell death in EBV-positive lymphoma cells illustrated in Fig. 6. Lytic gene expression will lead to cellular protein expression that provides signals for cell growth and tumorigenesis. In the presence of ATO, spontaneous and reagent-induced EBV reactivation is abolished, and involves decreased expression of EBV lytic genes by degradation of Zta, Rta and BMRF1 via sumoylation and ubiquitination. As a result, EBV cannot provide sufficient cell survival factors and results to cell death.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details 1 Department of Medicine, Section of Pulmonary Disease, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112, USA. 2 Department of Internal Medicine, Louisiana University School of Medicine, 1901 Perdido Street, New Orleans, LA 70112, USA. 3Department of Pathology and Laboratory, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112, USA. 4Department of Internal Medicine, University of Texas Medical Branch, 300 University Blvd, Galveston, TX 77550, USA. Received: 19 January 2017 Accepted: 12 JuneConclusions Most antiviral drugs have limited efficacy for treating EBV-related malignancies. ATO has received prior recognition as a cancer therapy due to its effectiveness in treating acute promyelocytic leukemia [47]. Several studies have shown that ATO may be useful for the treatment of other cancers such as ovarian, brain, breast, lung, gastric and cervical cancers [82?7]. However, its potential for the treatment of lymphoma has not been previously a.
