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

Authors

  • Pablo E. Vivas-Mejía,

    1. Department of Experimental Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, TX
    2. University of Puerto Rico Comprehensive Cancer Center, Rio Piedras, PR
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  • Bulent Ozpolat,

    1. Department of Experimental Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, TX
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  • Xian Chen,

    1. UNC-Duke Proteomics Center, University of North Carolina, Chapel Hill, NC
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  • Gabriel Lopez-Berestein

    Corresponding author
    1. Department of Experimental Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, TX
    • UT MD Anderson Cancer Center, Department of Experimental Therapeutics, Unit 422, 1515 Holcombe Blvd, Houston TX 77030, USA
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    • Fax: +1-713-792-0362.


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. © 2009 UICC

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