Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

Abstract

Epstein-Barr virus (EBV), a human gammaherpesvirus carried by more than 90% of the world's population, is associated with malignant tumors such as Burkitt's lymphoma (BL), Hodgkin lymphoma, post-transplant lymphoma, extra-nodal natural killer/T cell lymphoma, and nasopharyngeal and gastric carcinomas in immune-compromised patients. In the process of infection, EBV faces challenges: the host cell environment is harsh, and the survival and apoptosis of host cells are precisely regulated. Only when host cells receive sufficient survival signals may they immortalize. To establish efficiently a lytic or long-term latent infection, EBV must escape the host cell immunologic mechanism and resist host cell apoptosis by interfering with multiple signaling pathways. This review details the apoptotic pathway disrupted by EBV in EBV-infected cells and describes the interactions of EBV gene products with host cellular factors as well as the function of these factors, which decide the fate of the host cell. The relationships between other EBV-encoded genes and proteins of the B-cell leukemia/lymphoma (Bcl) family are unknown. Still, EBV seems to contribute to establishing its own latency and the formation of tumors by modifying events that impact cell survival and proliferation as well as the immune response of the infected host. We discuss potential therapeutic drugs to provide a foundation for further studies of tumor pathogenesis aimed at exploiting novel therapeutic strategies for EBV-associated diseases.

Disruption of Bcl-2 and Bcl-xL by viral proteins as a possible cause of cancer

“…Epstein-Barr virus (EBV) is a gammaherpesvirus carried by more than 90% of the world’s population, and it is associated with several lymphoid and epithelial malignancies, including Burkitt’s lymphoma, Hodgkin’s disease, and nasopharyngeal carcinoma [ 15 ] (Table 1 ). At least one homologue of the apoptotic inhibitor Bcl-2 is encoded by many gammaherpesviruses [ 16 ].…”

Apoptosis- and survival-related gene mRNA profile in peripheral blood leukocytes in children with acute EBV infectious mononucleosis

“…В литературе описаны продукты генома ВЭБ, которые могут как активировать, так и ингибировать экспрессию антиапоптотических факторов митохондриального пути апоптоза. Так, белок ВЭБ BZLF1 способен ингибировать экспрессию антиапоптотических факторов BCL-2 и BclXL в CD4 + T-клетках в ходе литической фазы ВЭБ-инфекции [22,32,54], а белок ВЭБ EBNA2 усиливает экспрессию антиапоптотических молекул BFL-1, BCL-XL, BCL-2 и MCL-1 в ходе пролиферации и иммортализации B-клеток [25,31,53].…”

“…В повышении уровня мРНК BCL-XL опосредованно участвует мембранный белок ВЭБ LMP2 (latent membrane protein 2), активируя транскрипционный фактор NF-κB, а также элементы Aktзависимого сигналинга [22,39,47], что приводит к повышению выживаемости клеток.…”

“…Известно, что продукты генома ВЭБ способны ингибировать сигнальные пути апоптоза, обеспечивая экранирование инфицированных клеток от воздействия иммунного ответа [22,45].…”

Role of Modulator of Inflammation Cyclooxygenase-2 in Gammaherpesvirus Mediated Tumorigenesis

“…Interestingly, COX-2 inhibitors have shown to down regulate Bcl-2 protein expression suppressing tumorigenesis (Tsujii and DuBois, 1995). The interactions of EBV coded proteins with Bcl-2 protein family has been summarized elsewhere which show that most of the Bcl-2 family members are targeted by EBV-coded proteins (Fu et al, 2013). KSHV encodes a viral homolog of Bcl-2 named as KS-Bcl-2, which inhibits apoptosis and autophagy when over expressed in cancer cells have recently been found to be essential for virus replication (Gallo et al, 2017).…”