Downregulation of the c-Myc target gene, peroxiredoxin III, contributes to arsenic trioxide-induced apoptosis in APL

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Arsenic trioxide (ATO) induces differentiation and apoptosis in acute promyelocytic leukemia (APL). Several reports indicate that in the APL-derived NB4 cells, apoptosis occurs in part by a mechanism that involves the inhibition of glutathione peroxidase, one of the enzymes that regulate the mitochondrial levels of H₂O₂, and that is present at low levels in these cells. Peroxiredoxin III (Prx III), a c-Myc target gene, is a mitochondria-specific H₂O₂-scavenger member of the thioredoxin-dependent peroxidases. NB4 cells express high levels of Prx III. We studied here the role of Prx III during ATO-induced apoptosis in NB4 cells. 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, promoted cytochrome-c release, and caspases activation. c-Myc was also down-regulated both at the protein and mRNA levels during ATO-induced apoptosis. Furthermore, depletion of c-Myc expression also induced a downregulation of Prx III. Therefore ATO-induced apoptosis provokes c-Myc downregulation which in turn, result in downregulation of Prx III. This cascade contributes to the mitochondria-dependent apoptotic events triggered by the accumulation of H₂O₂