Aminopeptidase-N/CD13 is a potential proapoptotic target in human myeloid tumor cells.
FASEB J
; 25(8): 2831-42, 2011 Aug.
Article
em En
| MEDLINE
| ID: mdl-21566207
ABSTRACT
The transmembrane metalloprotease aminopeptidase-N (APN)/CD13 is overexpressed in various solid and hematological malignancies in humans, including acute myeloid leukemia (AML) and is thought to influence tumor progression. Here, we investigated the contribution of APN/CD13 to the regulation of growth and survival processes in AML cells in vitro. Anti-CD13 monoclonal antibodies MY7 and SJ1D1 (which do not inhibit APN activity) and WM15 (an APN-blocking antibody) inhibited the growth of the AML cell line U937 and induced apoptosis, as evidenced by cell accumulation in the sub-G(1) phase, DNA fragmentation, and phosphatidylserine externalization. Isotype-matched IgG1 and the APN/CD13 enzymatic inhibitors bestatin and 2',3-dinitroflavone-8-acetic acid, were ineffective. Internalization of CD13-MY7 complex into cells was followed by mitochondrial membrane depolarization, Bcl-2 and Mcl-1 down-regulation, Bax up-regulation, caspase-9, caspase-8, and caspase-3 activation, and cleavage of the caspase substrate PARP-1. The broad-spectrum caspase inhibitor Z-VAD-fmk and the caspase-9- and caspase-8-specific inhibitors significantly attenuated apoptosis. CD13 ligation also induced apoptosis and PARP-1 cleavage in primary AML blasts, whereas normal blood cells were not affected. Overall, these data provide new evidence that CD13 can serve as a target for inducing caspase-dependent apoptosis in AML (independently of its APN activity). These findings may have implications for tumor biology and treatment.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
Antígenos CD13
Limite:
Adult
/
Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
FASEB J
Assunto da revista:
BIOLOGIA
/
FISIOLOGIA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
França