ROS-p38 MAPK-Fas/Fas Ligand-Linked Cascade Regulate Bax Translocation and Calcium Redistribution in Salubrinal-Induced Apoptosis of EBV-Transformed B Cells (46.49)

Abstract The small molecule salubrinal has antiviral activity against herpes simplex virus-1 (HSV-1) and inhibits dephosphorylation of eIF2 alpha. Salubrinal prevents vulnerable cells from going down the cell-death pathway and is deeply associated with ER stress. The Epstein-Barr Virus (EBV), also called human herpesvirus 4 (HHV-4), is a virus of the herpes family (which includes herpes simplex virus) and is one of the most common viruses in humans. However, maintaining hyper-phosphorylated eIF2α state with high doses of salubrinal treatment promotes apoptosis in some cancer cells. In this report, salubrinal inhibited proliferation and induced apoptosis of EBV-transformed B cells in both dose and time dependent manner. Notably, salubrinal induced ROS generation and p38 MAPK activation, which then induced expression of FasL. Moreover, salubrinal subsequently led to activation of caspases, calcium redistribution, Bax translocation, cytochrome c release, and apoptosis. Caspase inhibitors (z-VAD, z-IETD, and z-DEVD), p38 MAPK inhibitor (SB203580) and ROS inhibitor (NAC) recovered salubrinal-induced apoptosis. ZB4, an antagonistic anti-fas Ab, and SB203580 effectively blocked apoptosis without exerting any influence on ROS generation. These findings suggest that salubrinal may be a novel therapeutic approach for EBV-associated malignant diseases.