Sorafenib (SRF) is a multi-kinase inhibitor that has been shown to have antitumor activity against several types of cancers, but the effect of SRF on EBV-transformed B cells is unknown. We report that SRF can induce the apoptosis of EBV-transformed B cells through JNK/p38-MAPK activation. SRF triggered the generation of reactive oxygen species (ROS), translocation of Bax into the mitochondria, disruption of mitochondrial membrane potential, activation of caspase-9, caspase-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. N-acetyl-l-cysteine (NAC) inhibited the activation of JNK and p38-MAPK. SP600125 and SB203580 blocked apoptosis and mitochondrial membrane disruption but did not affect ROS production after SRF treatment. These findings provide novel insights into the molecular mechanisms driving SRF-mediated cell death and suggest that SRF could be a potential therapeutic drug for the treatment of EBV-related malignant diseases.

Dexamethasone (Dex) inhibits the growth of diverse types of cancer cells and is utilized clinically for the therapy of hematological malignancies. In this study, we investigated the molecular mechanisms of Dex action in the apoptosis of Epstein-Barr virus (EBV)-transformed B cells. We showed that Dex inhibited the proliferation of EBV-transformed B cells and induced apoptosis by activating caspase-9, -3 and -8. While activation of caspase-9 was triggered as early as 2 h after Dex treatment, cleavage of caspase-8 was deferred and was found 8 h after the exposure. Dex-dependent activation of caspase-8 was blocked by the specific caspase-9 inhibitor, z-LEHD-fmk. Moreover, Dex significantly increased the expression of X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) and induced the translocation of XAF1 into the cytosol. Cytosolic XAF1 with Puma induced the translocation of Bax into mitochondria. Dex led to up-regulation of reactive oxygen species (ROS) generation and the phosphorylation of ERK1/2 after the exposure. We speculated that ROS generation might be the first event of Dex-induced apoptosis because ROS inhibitor NAC abrogated ROS production and ERK1/2 activation, but PD98059 did not block ROS production. NAC and PD98059 also suppressed the translocation of XAF1, Puma and Bax into mitochondria. These results demonstrated that Dex-mediated activation of caspase-9 via ROS generation and ERK1/2 pathway activation resulted in the activation of caspase-8 and the increment of XAF1, thereby induced apoptosis of EBV-transformed B cells. These findings suggest that Dex constitutes a probable therapy for EBV-associated hematological malignancies.

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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.