Downregulation of the c-MYC target gene, peroxiredoxin III, contributes to arsenic trioxide-induced apoptosis in acute promyelocytic leukemia
✍ Scribed by Pablo E. Vivas-Mejía; Bulent Ozpolat; Xian Chen; Gabriel Lopez-Berestein
- Book ID
- 102274312
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- French
- Weight
- 484 KB
- Volume
- 125
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Abstract
Arsenic trioxide (ATO) induces differentiation and apoptosis in acute promyelocytic leukemia (APL). Several reports indicate that in APL cells apoptosis occurs mainly by a mechanism that involves the inhibition of glutathione peroxidase, one of the enzymes that regulates mitochondrial levels of H~2~O~2~. Peroxiredoxin (Prx) III, a c‐MYC target gene, is also a mitochondria‐specific H~2~O~2~‐scavenger enzyme. We studied here the role of Prx III during ATO‐induced apoptosis in APL‐derived NB4 cells, since these cells express high levels of Prx III. The protein and mRNA levels of Prx III decreased during ATO‐induced apoptosis of NB4 cells. The downregulation of Prx III occurred before reactive oxygen species accumulation, reduction in the mitochondrial membrane potential and apoptosis. Depletion of Prx III enhanced mitochondrial‐dependent apoptosis events. In contrast, overexpression of Prx III led to reduced levels of ATO‐induced apoptosis. c‐MYC was also downregulated in ATO‐treated NB4 cells. Furthermore, depletion of c‐MYC also reduced the Prx‐III expression levels. Finally chromatin immunoprecipitation and luciferase reporter assays confirmed that downregulation of Prx‐III was caused by the reduction of c‐MYC levels during ATO‐induced apoptosis of NB4 cells. These findings demonstrate a novel apoptotic‐response pathway whereby downregulation of Prx‐III potentiates ATO‐induced apoptosis in APL cells. © 2009 UICC