Sodium selenite-induced reactive oxygen species generation is an early event that triggers endoplasmic reticulum stress mitochondrial apoptotic pathways in NB4 cells.

Here we report the novel function of heat shock protein 90 in regulating autophagy and apoptosis in human acute promyelocytic leukemia (APL)-derived NB4 cells, via decreased nuclear factor-κB activity and nucleus translocation, thus leading to down-regulation of autophagy-related component Beclin1. This study may be helpful in understanding the detail mechanism for sodium selenite in APL therapy.

Edited by Vladimir Skulachev Keywords:Manganese superoxide dismutase Reactive oxygen species Extracellular regulated kinase Nuclear translocation p53 a b s t r a c t Following our previous finding that sodium selenite induces apoptosis in human leukemia NB4 cells, we now show that the expression of the critical antioxidant enzyme manganese superoxide dismutase (MnSOD) is remarkably elevated during this process. We further reveal that reactive oxygen species (ROS), especially superoxide radicals, play a crucial role in selenite-induced MnSOD upregulation, with extracellular regulated kinase (ERK) and p53 closely implicated. Specifically, ERK2 translocates into the nucleus driven by ROS, where it directly phosphorylates p53, leading to dissociation of p53 from its inhibitory protein mouse double minute 2 (MDM2). Active p53 directly mediates the expression of MnSOD, serving as the link between ERK2 translocation and MnSOD upregulation.

The attenuated Japanese encephalitis virus (JEV) strain SA14-14-2 has been successfully utilized to prevent JEV infection; however, the attenuation determinants have not been fully elucidated. The envelope (E) protein of the attenuated JEV SA14-14-2 strain differs from that of the virulent parental SA14 strain at eight amino acid positions (E107, E138, E176, E177, E264, E279, E315, and E439). Here, we investigated the SA14-14-2-attenuation determinants by mutating E107, E138, E176, E177, and E279 in SA14-14-2 to their status in the parental virulent strain and tested the replication capacity, neurovirulence, neuroinvasiveness, and mortality associated with the mutated viruses in mice, as compared with those of JEV SA14-14-2 and SA14. Our findings indicated that revertant mutations at the E138 or E107 position significantly increased SA14-14-2 virulence, whereas other revertant mutations exhibited significant increases in neurovirulence only when combined with E138, E107, and other mutations. Revertant mutations at all eight positions in the E protein resulted in the highest degree of SA14-14-2 virulence, although this was still lower than that observed in SA14. These results demonstrated the critical role of the viral E protein in controlling JEV virulence and identified the amino acids at the E107 and E138 positions as the key determinants of SA14-14-2 neurovirulence.

Selenium at low concentrations has a chemopreventive role against cancer, while at high concentrations, selenite exerts a direct antitumor effect. However, the mechanisms behind these effects remain elusive. In this study, we found that different concentrations of selenite triggered different signal pathways in human leukemia NB4 cells. Low concentrations of selenite elicited mild endoplasmic reticulum (ER) stress and mediated cell survival by activating unfolded protein response signaling, whereas high concentrations of selenite induced severe ER stress and caused cell death by activation of the pro-apoptotic transcription factors GADD153. In addition, selenite at low concentrations activated other anti-apoptotic pathways, such as AKT and ERK, whereas high concentrations of selenite induced activation of p53 and oxidative stress, which mediated the antitumor activity of selenite by causing mitochondrial dysfunction and caspase activation. These findings uncover the molecular mechanisms of the chemopreventive and antitumor effects of different concentrations of selenite.