Downregulation of the c-MYC target gene, peroxiredoxin III, contributes to arsenic trioxide-induced apoptosis in acute promyelocytic leukemia.
Enviado por Pablo Vivas-Mejia el
Título | Downregulation of the c-MYC target gene, peroxiredoxin III, contributes to arsenic trioxide-induced apoptosis in acute promyelocytic leukemia. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Autores | Vivas-Mejia, P, Ozpolat, B, Chen, X, Lopez-Berestein, G |
Journal | Int J Cancer |
Volume | 125 |
Issue | 2 |
Pagination | 264-75 |
Date Published | 2009 Jul 15 |
ISSN | 1097-0215 |
Palabras clave | Apoptosis, Arsenicals, Base Sequence, Cell Line, Tumor, Chromatin Immunoprecipitation, DNA Primers, Down-Regulation, Genes, myc, Humans, Leukemia, Promyelocytic, Acute, Oxides, Peroxiredoxins, Reactive Oxygen Species, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, RNA, Small Interfering |
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. |
DOI | 10.1002/ijc.24341 |
Alternate Journal | Int. J. Cancer |
PubMed ID | 19408305 |
Grant List | 5P30CA016672-29 / CA / NCI NIH HHS / United States U54CA96300 / CA / NCI NIH HHS / United States |