Downregulation of Peroxiredoxin III Contributes to Arsenic Trioxide-Induced Apoptosis in APL.

Arsenic trioxide (ATO) induces differentiation and apoptosis in acute promyelocytic leukemia (APL). Compared with other leukemia cells, the APL-derived NB4 cells are particularly sensitive to ATO-induced apoptosis. Several reports indicate that in NB4 cells, apoptosis occurs in part by a mechanism that involves the inhibition of glutathione peroxidase, one of the enzymes that regulate the levels of H₂O₂ in the mitochondria, and that is present only at low levels in NB4 cells. Peroxirredoxin III (Prx III) is a mitochondria-specific H₂O₂-scavenger member of the thioredoxin-dependent peroxidases. NB4 cells express high levels of Prx III; however the role of Prx III in ATO-induced apoptosis in NB4 cells has not been investigated. We studied here whether Prx III is regulated during ATO-induced apoptosis in NB4 cells and whether the depletion of Prx III further sensitized these cells to ATO-induced apoptosis. The protein and mRNA levels of Prx III were decreased during ATO-induced apoptosis of NB4 cells. The down-regulation of Prx III occurred prior to the accumulation of reactive oxygen species, reduction in the mitochondrial membrane potential and apoptosis. Depletion of Prx III enhanced the ATO-induced mitochondrial damage, and also promoted cytochrome-c release, and caspase-3 and caspase-9 activation. Prx III is downregulated early during ATO-induced apoptosis, facilitating in this way the mitochondria-depending apoptotic events triggered by the accumulation of H₂O₂.