siRNA targeting LMP1-induced apoptosis in EBV-positive lymphoma cells is associated with inhibition of telomerase activity and expression

Mechanisms of cell immortalization mediated by EB viral activation of telomerase in nasopharyngeal carcinoma

“…EBV may cause the NPC cell oncogenic clonal evolution by interfering with several intracellular mechanisms in the npg infected cells [1,[7][8][9][10][11]. Recently, evidence suggests that the enzyme telomerase required for cell immortalization is activated in NPC and the EBV proteins are involved in regulating telomerase activity [12][13][14], consistent with the findings that EBV proteins also play a key role in immortalization of infected B-lymphocyte [15][16][17]. Here we review the recent progress in our understanding of regulation of telomerase activity by EBV proteins, a critical step in cell immortalization.…”

“…In both primary human nasopharyngeal epithelial cell culture and NPC cell lines, telomerase is stimulated by expression of LMP1 in association with increased gene expression of c-myc [14,15]. Withdrawal or suppression of LMP1 expression decreases telomerase activity and c-myc transactivation, suggesting a causative relationship between LMP1 and hTERT [14,15].…”

“…In both primary human nasopharyngeal epithelial cell culture and NPC cell lines, telomerase is stimulated by expression of LMP1 in association with increased gene expression of c-myc [14,15]. Withdrawal or suppression of LMP1 expression decreases telomerase activity and c-myc transactivation, suggesting a causative relationship between LMP1 and hTERT [14,15]. Blocking c-myc gene expression or mutating the cmyc-responsive E-box elements in the minimal core of hTERT promoter inhibits the hTERT expression induced by LMP1, pointing to a c-myc-dependent transactivation of the hTERT gene by LMP1 [14] (Figure 3).…”

“…However, what is not yet clear includes the protein motifs that mediate the molecular interactions between the hTERT and NF-κB p65 proteins, and the biological consequence of LMP1 signalling in the maintenance of telomeres. Nonetheless, recent studies attempting to target LMP1 have shown that silencing LMP1 by siRNA induces apoptosis in EBV-positive lymphoma cells in association with telomerase inhibition, suggesting that molecular targeting of LMP1 may be of therapeutic value in EBV-associated tumours [15]. These concepts may be reinforced by the data that expression of hTERT alone immortalizes non-malignant nasopharyngeal epithelial [12].…”

Treating autoimmune demyelination by augmenting lymphocyte apoptosis in the central nervous system

“…Therefore, therapies that induce apoptosis in EBV-infected B cells in the CNS might disinhibit activation-induced T-cell apoptosis in the CNS in MS by reducing the costimulatory antiapoptotic signals available to the T cells. Therapeutic approaches to eliminating EBV-infected B cells include: rituximab, which deletes EBV-infected B cells as well as other CD20-expressing B cells; the transfer of autologous EBVspecific cytotoxic T cells (Savoldo et al, 2006); and targeting small interfering RNA to the EBV-encoded latent membrane protein 1 (Mei et al, 2006), which plays a key role in EBV infection of B cells by mimicking an activated CD40 receptor.…”