cytochrome-c-t and Epstein-Barr-Virus-Infections

The inhibitors of apoptosis (IAP) are important regulators of apoptosis. However, little is known about the capacity of Smac mimetics (IAP inhibitor) to overcome virally associated-lymphoma's (VAL) resistance to apoptosis. Here, we explored the pro-apoptotic effect of a novel Smac mimetic, RMT5265.2HCL (RMT) in VAL cells. RMT improved the sensitivity to apoptosis in EBV- and to some extend in HTLV-1- but not in HHV-8-VAL. Furthermore, we identified that RMT promotes caspase 3 and 9 cleavage by inhibiting XIAP and inducing the mitochondrial efflux of Smac and cytochrome C. This investigation further support exploring the use of Smac inhibitors in VAL.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Biomimetics; Cell Line, Tumor; Cell Transformation, Viral; Cytochromes c; Deltaretrovirus Infections; Dipeptides; Epstein-Barr Virus Infections; HEK293 Cells; Herpesvirus 4, Human; Human T-lymphotropic virus 1; Humans; Intracellular Signaling Peptides and Proteins; Lymphoma, T-Cell; Mice; Mice, Transgenic; Mitochondria; Mitochondrial Proteins; Models, Biological; Tetrazoles; Up-Regulation; X-Linked Inhibitor of Apoptosis Protein

EBV (Epstein-Barr virus) is considered to be a major factor that causes NPC (nasopharyngeal carcinoma), which is one of the sneakiest cancers frequently occurring in Southeast Asia and Southern China. Apoptosis and pro-apoptotic signals have been studied for decades; however, few have extended the prevailing view of EBV to its impact on NPC in perspective of apoptosis. One of the important proteins named VDAC1 (voltage-dependent anion protein 1) on the mitochondrial outer membrane controls the pro-apoptotic signals in mammalian cells. The impact of EBV infection on VDAC1 and related apoptotic signals remains unclear. In order to study the VDAC1's role in EBV-infected NPC cells, we employ siRNA (small interfering RNA) inhibition to analyse the release of Ca2+ and Cyto c (cytochrome c) signals in the cytoplasm, as they are important pro-apoptotic signals. The results show a decrease of Ca2+ release and up-regulation of Cyto c with EBV infection. After siRNA transfection, the dysregulation of Cyto c is neutralized, which is evidence that the level of Cyto c release in virus-infected NPC cells is the as same as that of non-infected NPC cells. This result indicates that EBV infection changes the cytoplasmic level of Cyto c through regulating VDAC1. In summary, this study reports that EBV changes the release of Ca2+ and Cyto c in the cytoplasm of NPC cells, and that Cyto c changes are mediated by VDAC1 regulation.

Topics: Calcium; Carcinoma; Cell Line, Tumor; Cytochromes c; Cytoplasm; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Ions; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; RNA Interference; RNA, Small Interfering; Signal Transduction; Up-Regulation; Voltage-Dependent Anion Channel 1

Epstein-Barr virus (EBV) is known to be a causative agent of hemophagocytic lymphohistiocytosis (HLH). To investigate association of apoptosis in the pathogenesis of EBV-associated HLH, the serum EBV loads, and serum concentrations of soluble tumor necrosis factor receptor 1 (sTNF-R1), soluble Fas ligand, and cytochrome c were examined in 15 patients with EBV-associated HLH and 24 patients with infectious mononucleosis (IM). Levels of sTNF-R1 are known to reflect the biological activity of TNF-alpha and cytochrome c is a specific marker of apoptosis. EBV loads, and concentrations of sTNF-R1 and cytochrome c were significantly higher in patients with EBV-associated HLH than in patients with IM. On the other hand, there were no statistically significant differences in the concentrations of soluble Fas ligand. In patients with EBV-associated HLH, EBV loads, concentrations of sTNF-R1, and cytochrome c were correlated with each other. These results suggest that apoptosis, which is dependent on the EBV load and could be mediated by TNF-alpha, plays a major role in the pathophysiology of EBV-associated HLH.

Topics: Apoptosis; Child, Preschool; Cytochromes c; Epstein-Barr Virus Infections; Fas Ligand Protein; Female; Humans; Lymphohistiocytosis, Hemophagocytic; Male; Membrane Glycoproteins; Receptors, Tumor Necrosis Factor, Type I; Statistics as Topic; Tumor Necrosis Factors; Viral Load