Endoscopy 2005; 37 - A31
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

GA Doherty 1, 2, SM Byrne 1, 2, ES Molloy 3, CM Cox 1, NM Griffin 1, SC Austin 1, EW Kay 4, FE Murray 2, 3, DJ Fitzgerald 1
  • 1Department of Molecular Medicine, Conway Institute, University College Dublin
  • 2Department of Gastroenterology
  • 3Department of Clinical Pharmacology
  • 4Department of Histopathology, Beaumont Hospital and Royal College of Surgeons in Ireland

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.