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DOI: 10.1055/s-2005-922893
Regulation of cell cycle progression by cyclooxygenase-2 in colorectal cancer; the role of the EP4 receptor, a novel therapeutic target
Aims: Cyclooxygenase-2 (COX-2) expression is elevated in colorectal cancer (CRC) and is associated with poor survival for reasons which are not well characterised. We assessed the mechanisms by which COX-2 might regulate cell cycle progression in a colon cancer cell line.
Results: HT-29 colon cancer cells produce PGE2 in a COX-2 dependent manner. An accumulation of cells in G0/G1 phase of the cell cycle is observed on treatment with SC-236 5mM (selective COX-2 inhibitor) for 24 hours (p=0.02). The effects of the COX-2 inhibitor are abrogated by co-incubation with PGE2 (1mM). G0/G1 arrest is also seen with a specific antagonist of the EP4 receptor (EP4A, L-161982) (p=0.01). EP4 is the most abundant subtype of PGE2 receptor in HT-29 cells (and in a panel of colorectal tumours, n=10) as demonstrated by quantitative RT-PCR. Treatment of HT-29 cells with either SC-236 or EP4A causes an early reduction in intracellular cAMP (ANOVA, p=0.01) consistent with a common signalling mechanism.
Conclusions: COX-2 regulates cell cycle transition via signalling through the EP4 receptor; the most abundant PGE2 receptor in colorectal tumours. Specific targeting of this pathway may offer a safer alternative to COX-2 inhibition in the prevention and treatment of CRC.