In bcr-abl-positive myeloid cells resistant to conventional chemotherapeutic agents, expression of Par-4 increases sensitivity to imatinib (STI571) and histone deacetylase-inhibitors.
Biochem Pharmacol
; 68(1): 85-93, 2004 Jul 01.
Article
en En
| MEDLINE
| ID: mdl-15183120
ABSTRACT
In a variety of malignant cells the prostate-apoptosis-response-gene-4 (Par-4) induces increased sensitivity towards chemotherapeutic agents by down-regulating anti-apoptotic B-cell lymphoma-gene 2 (Bcl-2). Hypothesizing that Par-4 also influences apoptosis in myeloid cell lines, we tested this hypothesis by stably transfecting bcr-abl transformed-K562 cells with a Par-4-expressing vector. Here we demonstrate that over-expression of Par-4 in K562 cells up-regulates expression levels of Bcl-2 and death-associated protein (Daxx). Upon treatment with different chemotherapeutic agents, Fas- or TRAIL agonistic antibodies, Par-4-positive cells did not exhibit an increased rate of apoptosis as compared to Par-4-negative control cells. However, incubation with histone deacetylase (HDAC)-inhibitors Trichostatin A (TSA) and LAQ824 or the tyrosinkinase inhibitor Imatinib (STI571) increased the rate of apoptosis in Par-4-positive K562 cells. Assessing the underlying molecular mechanisms for the Par-4-induced response to HDAC-inhibitors and STI571 we provide evidence, that these effects are associated with a down-regulation of Daxx, enforced activation of caspases and enhanced cleavage of cellular inhibitor of apoptosis (cIAP)-1 and -2.
Buscar en Google
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Pirimidinas
/
Proteínas Portadoras
/
Apoptosis
/
Péptidos y Proteínas de Señalización Intracelular
/
Inhibidores Enzimáticos
/
Inhibidores de Histona Desacetilasas
Tipo de estudio:
Diagnostic_studies
Límite:
Humans
/
Male
Idioma:
En
Revista:
Biochem Pharmacol
Año:
2004
Tipo del documento:
Article
País de afiliación:
Alemania