Sorafenib induces apoptosis through reactive oxygen species production, JNK/p38 MAPK activation, and suppression of Akt/NF-kB signaling in EBV-transformed B cells (P2088)

Abstract

Sorafenib (SRF), the multiple tyrosine kinase inhibitor, is known as a potential targeted drug that may have antitumor activity against various cancers, but the roles of SRF in EBV-transformed B cells remain unclear. Here, we investigated the in vitro cytotoxic effects of SRF on EBV-transformed B cells and the underlying mechanism such as the changes in oxidative stress and MAPKs signaling, which are closely associated with cell death-signaling transduction pathways, in EBV-transformed B cells treated with SRF. We first observed that SRF significantly decreased the cell viability of EBV-transformed B cells in a dose-dependent manner. SRF induced the generation of reactive oxygen species (ROS), translocation of Bax into mitochondria, disruption of mitochondrial membrane potential, activation of caspase-9, -3, and PARP, and subsequent apoptosis. Moreover, we found that SRF exposure activated the phosphorylation of JNK and p38 MAPK and suppressed the phosphorylation of PI3K p85 and Akt. In particular, SRF diminished nuclear localization of NF-κB in EBV-transformed B cells. These results demonstrate that SRF induces apoptosis through ROS production, ER stress, and mitochondrial-dependent pathway in EBV-transformed B cells. Taken together, these findings provide an overview of the molecular signaling pathway driving SRF-mediated cell death in EBV-transformed B cells and suggest SRF could be a potential therapeutic drug for the treatment of EBV-transformed B cells.