ROS and ERK1/2-mediated caspase-9 activation increases XAF1 expression in dexamethasone-induced apoptosis of EBV-transformed B cells

Abstract

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.

Inhibition of Uncoupling Protein 2 Attenuates Cardiac Hypertrophy Induced by Transverse Aortic Constriction in Mice

“…Attenuation of ATP decrease after TAC by UCP2 knockout, as shown in the current study, apparently could result in cardioprotection. In contrast to the connection between cell apoptosis and ROS [26,27], we showed increased ROS, but not increased apoptosis after TAC, possibly due to enhanced oxygen utilization after UCP2 knockout [28]. Exact mechanisms underlying such discrepancy, however, needs further studies.…”

Berberine induces mitochondrial apoptosis of EBV-transformed B cells through p53-mediated regulation of XAF1 and GADD45α

“…ROS act as an early signal activator to provoke apoptosis in vinca alkaloid-treated lung adenocarcinoma cells (53). In our previous report, we proposed that ROS generation might be the initiating event in the translocation of XAF1 and phosphorylation of ERK1/2 in dexamethasone-induced apoptosis of EBV-transformed B cells (54). Likewise, NAC, p38 inhibitor, and JNK inhibitors significantly inhibited berberine-induced apoptosis by restoration of proapoptotic proteins, including PUMA, phosphorylated Bax, and phosphorylated Bim to control levels and completely blocked the upregulation of XAF1, GADD45α, and phosphorylation of p53.…”

Foot-and-mouth disease virus infection of dendritic cells triggers phosphorylation of ERK1/2 inducing class I presentation and apoptosis

“…Since FMDV induces apoptosis of DCs [12] and that ERK1/2 is associated to the activation of caspase-9 [26], we decided to analyze this fact on murine conventional DCs differentiated from murine bone marrow (Fig. 2A).…”