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

Abstract

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.