• RSV LRTD may actually be a heterogeneous disease. 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 STK17β, 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, R(2)=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. Colorectal cancer (CRC) remains a leading cause of cancer death, with worldwide one million new cases each year and as many as half a million cancer deaths annually (Boyle and Leon, 2002) . Cyclooxygenase-2 (COX-2) expression is increased in the majority of colorectal tumours (Eberhart et al, 1994) and this induction is associated with advanced tumour stage and correlates with poor clinical outcomes (Sheehan et al, 1999) . Nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX activity, show anti-neoplastic effects in vitro (Richter et al, 2001; Sheng et al, 1997) and human studies have demonstrated their use to be associated with a reduced incidence of colorectal neoplasia Sandler et al, 2003) . Although more recent studies have confirmed the chemopreventive activity of COX-2selective NSAIDs (Arber et al, 2006; Baron et al, 2006; Bertagnolli et al, 2006) , it is also clear that their long-term use is associated with an unacceptable increase in the risk of cardiovascular events (Bertagnolli et al, 2006; Bresalier et al, 2005) .