bay-11-7082 and Epstein-Barr-Virus-Infections

EBV-associated gastric carcinoma (EBVaGC) is a specific subgroup of gastric carcinoma, and the multifunctional transcriptional factor NF-κB may contribute to its tumorigenesis. In this study, we comprehensively characterized NF-κB signaling in EBVaGC using qRT-PCR, western blot, immunofluorescence assays, ELISA, and immunohistochemistry staining. NF-κB-signaling inhibitors may inhibit the growth of EBVaGC cells and induce significant apoptosis. IκBα is a key regulatory molecule, and repression of IκBα can contribute to aberrant NF-κB activation. Overexpression of LMP1 and LMP2A in the EBV-negative GC cell line SGC7901 could inhibit the expression of IκBα and induce NF-κB activation. These findings indicate that the canonical NF-κB signal is constitutively activated and plays an important role in EBVaGC tumorigenesis.

Topics: Carcinogenesis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Gene Expression Regulation, Neoplastic; Herpesvirus 4, Human; Humans; Leupeptins; NF-kappa B; NF-KappaB Inhibitor alpha; Nitriles; RNA, Small Interfering; Signal Transduction; Stomach Neoplasms; Sulfones; TNF Receptor-Associated Factor 1; Viral Matrix Proteins

Epstein-Barr virus (EBV) infection in tumor cells is generally restricted to the latent forms of viral infection. Switching the latent form of viral infection into the lytic form may induce tumor cell death. An important nuclear factor, nuclear factor (NF)-kappaB, is thought to play an essential role in EBV lytic infection; high levels of NF-kappaB can inhibit EBV lytic replication. In this study, we tested the effect of inducing EBV lytic replication using two NF-kappaB inhibitors: Bay11-7082 and Z-LLF-CHO, to reveal the possibility of targeting EBV-positive cancer therapy with these two NF-kappaB inhibitors. Our results showed that Bay11-7082 and Z-LLF-CHO reactivated EBV in a dose-dependent manner, thus resulting in EBV-positive 5-8F cell death. In contrast, there was no significant effect on EBV-negative HNE3 cells. When ganciclovir was used in combination with either Bay11-7082 or Z-LLF-CHO to treat 5-8F cells, the cytotoxic effect of the NF-kappaB inhibitor was amplified. The finding indicates that inhibiting the NF-kappaB activity of EBV-positive cells can induce lytic replication of EBV and cause lytic cytotoxicity against these cells.

Topics: Antiviral Agents; Cell Line, Tumor; Cell Nucleus; Cytoplasm; Epstein-Barr Virus Infections; Ganciclovir; Herpesvirus 4, Human; Humans; Nasopharyngeal Neoplasms; NF-kappa B; Nitriles; Oligopeptides; Sulfones; Transcription Factor RelA; Virus Activation