Downregulation of the c-MYC target gene, peroxiredoxin III, contributes to arsenic trioxide-induced apoptosis in acute promyelocytic leukemia

Pablo E. Vivas-Mejía, Bulent Ozpolat, Xian Chen, Gabriel Lopez-Berestein

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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 H2O2. Peroxiredoxin (Prx) III, a c-MYC target gene, is also a mitochondria-specific H2O2-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.

Original languageEnglish (US)
Pages (from-to)264-275
Number of pages12
JournalInternational Journal of Cancer
Volume125
Issue number2
DOIs
StatePublished - Jul 15 2009

Keywords

  • Apoptosis
  • Arsenic
  • c-MYC
  • Mitochondria
  • Peroxiredoxins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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