DRAK2 a Novel Effector of Apoptosis is Modulated by Cyclooxygenase 2 in Colorectal Cancer

Aims: Cyclooxygenase 2 (COX-2) is over-expressed in the majority of colorectal tumours, and cancer cells that express COX-2 appear to be rendered resistant to apoptosis. The mechanisms by which COX-2 modulates apoptosis have not been well characterised, however we have identified DRAK2, a pro-apoptotic serine/threonine kinase, as regulated by COX-2 in cancer cells.

Results: DRAK2 was identified by triplicate oligonucleotide microarrays as consistently upregulated in HCA7 cells following treatment with SC-236, a selective COX-2 inhibitor. Quantitative PCR confirmed this induction of DRAK-2 transcription (4.4 fold increase, p=0.02), an effect that was reversed by co-treatment with PGE2. Upregulation of DRAK2 protein in HCA7 cells was confirmed by immunoflourescence microcopy. DRAK2 mRNA levels are suppressed in human colorectal tumours (n=10) relative to normal colorectal mucosa (50% decrease, p=0.001). Treatment of patients with colorectal cancer (n=5) with rofecoxib for 5–7 days causes upregulation of DRAK2 mRNA levels in tumour tissue (2.6 fold increase, p=0.004). DRAK2 is highly expressed in Jurkat cells and silencing of DRAK2 expression in these cells by RNA interference renders Jurkat cells resistant to staurosporine induced apoptosis.

Conclusions: DRAK-2, a novel pro-apoptotic kinase, is regulated both in-vitro and in-vivo by COX-2 and may explain some of the antineoplastic activity of COX-2 inhibitors.