Downregulation of the c-MYC target gene, peroxiredoxin III, contributes to arsenic trioxide-induced apoptosis in acute promyelocytic leukemia.
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.
Vivas-Mejía
Pablo E
PE
Department of Experimental Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
Ozpolat
Bulent
B
Chen
Xian
X
Lopez-Berestein
Gabriel
G
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D015536:Down-Regulation; D016259:Genes, myc; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D054464:Peroxiredoxins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001152:Arsenicals; D017931:DNA Primers; D010087:Oxides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D054464:Peroxiredoxins; D000077237:Arsenic Trioxide