Regulation of the apoptosis-inducing kinase DRAK2 by cyclooxygenase-2 in colorectal cancer.
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.


CONCLUSIONS
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.
Doherty
G A
GA
Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. glen_doherty@hotmail.com
Byrne
S M
SM
Austin
S C
SC
Scully
G M
GM
Sadlier
D M
DM
Neilan
T G
TG
Kay
E W
EW
Murray
F E
FE
Fitzgerald
D J
DJ
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000502:physiology*; D015232:Dinoprostone / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D034622:RNA Interference
D051017:Apoptosis Regulatory Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D017346:Protein Serine-Threonine Kinases; C115489:STK17B protein, human; D015232:Dinoprostone