Doherty G A, Byrne S M, Austin S C, Scully G M, Sadlier D M, Neilan T G, Kay E W, Murray F E, Fitzgerald D J
Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
Br J Cancer. 2009 Aug 4;101(3):483-91. doi: 10.1038/sj.bjc.6605144.
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.
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.
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.
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.
环氧化酶-2（COX-2）在结直肠癌（CRC）中过度表达，使肿瘤细胞对凋亡产生抗性。选择性COX-2抑制在CRC预防中有效，尽管有不良心血管影响，因此重点已转向下游途径。
微阵列实验鉴定了HCA7 CRC细胞中受COX-2调控的基因。通过qRT-PCR验证了COX-2在体外和体内对DRAK2（DAP激酶相关凋亡诱导激酶2或STK17β，一种凋亡诱导激酶）的调控。
COX-2抑制诱导HCA7细胞凋亡并增强DRAK2表达（qRT-PCR显示4小时时增加4.4倍，P = 0.001），PGE(2)共同给药可阻止该效应。与正常黏膜相比，一组人类结直肠癌（n = 10）中DRAK2水平受到抑制，并且与COX-2表达呈负相关（R = -0.68，R2 = 0.46，P = 0.03）。给CRC患者（n = 5）施用选择性COX-2抑制剂罗非昔布可诱导肿瘤中DRAK2表达（增加2.5倍，P = 0.01）。RNAi体外沉默DRAK2可增强COX-2抑制剂处理后CRC细胞的存活。
DRAK2是一种丝氨酸 - 苏氨酸激酶，参与凋亡调控，在体外和体内均受COX-2负调控，提示COX-2影响癌细胞存活的新机制。
