Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer.
Br J Cancer
; 101(3): 483-91, 2009 Aug 04.
Article
em En
| MEDLINE
| ID: mdl-19638987
ABSTRACT
BACKGROUND:
Cyclooxygenase-2 (COX-2) is over-expressed in colorectal cancer (CRC), rendering tumour cells resistant to apoptosis. Selective COX-2 inhibition is effective in CRC prevention, although having adverse cardiovascular effects, thus focus has shifted to downstream pathways.METHODS:
Microarray experiments identified genes regulated by COX-2 in HCA7 CRC cells. In vitro and in vivo regulation of DRAK2 (DAP kinase-related apoptosis-inducing kinase 2 or STK17beta, an apoptosis-inducing kinase) by COX-2 was validated by qRT-PCR.RESULTS:
Inhibition of COX-2 induced apoptosis and enhanced DRAK2 expression in HCA7 cells (4.4-fold increase at 4 h by qRT-PCR, P=0.001), an effect prevented by co-administration of PGE(2). DRAK2 levels were suppressed in a panel of human colorectal tumours (n=10) compared to normal mucosa, and showed inverse correlation with COX-2 expression (R=-0.68, R2=0.46, P=0.03). Administration of the selective COX-2 inhibitor rofecoxib to patients with CRC (n=5) induced DRAK2 expression in tumours (2.5-fold increase, P=0.01). In vitro silencing of DRAK2 by RNAi enhanced CRC cell survival following COX-2 inhibitor treatment.CONCLUSION:
DRAK2 is a serine-threonine kinase implicated in the regulation of apoptosis and is negatively regulated by COX-2 in vitro and in vivo, suggesting a novel mechanism for the effect of COX-2 on cancer cell survival.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Problema de saúde:
6_colon_rectum_cancers
Assunto principal:
Neoplasias Colorretais
/
Proteínas Serina-Treonina Quinases
/
Apoptose
/
Ciclo-Oxigenase 2
/
Proteínas Reguladoras de Apoptose
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Br J Cancer
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Irlanda