Non-steroidal anti-inflammatory drugs (NSAIDs) prevent colorectal cancer, but their anticancer mechanism has not been resolved. In Science, Maria Domenica Castellone et al. report that by blocking the activity of the pro-inflammatory cyclooxygenase 2 (COX2) enzyme, NSAIDs interfere with a G-protein-coupled-receptor signalling pathway that normally promotes cell proliferation.

NSAIDs inhibit two enzymes that are involved in prostaglandin synthesis (COX1 and COX2), and can reduce the number and size of adenomas in patients with familial adenomatosis polyposis — a cancer predisposition syndrome associated with mutations in the adenomatosis polyposis coli gene (APC). NSAIDs also prevent colon cancer in the APCmin mouse model of this disease. Many studies have implicated the contribution of COX2 and one of its metabolites, prostaglandin E2 (PGE2) in colon cancer development, so Castellone set out to identify a link between PGE2 and APC-regulated signalling pathways.

PGE2 is a mitogen in colon cancer cells that carry inactivating mutations in APC. In a search for downstream mediators of APC signalling that are affected by treatment of colon cancer cells with PGE2, Castellone found that this prostaglandin increased the transcriptional activity of β-catenin. Sorting the pathway out piece by piece, they discovered that PGE2 activates one of its receptors, EP2, which is linked to a heterotrimeric G-protein that consists of α, β and γ subunits. On receptor activation, these G-protein subunits dissociate. Free Gα interacts with axin, a scaffold protein that forms a large molecular complex with APC. This interaction causes the complex to release glycogen synthase kinase 3β (GSK3β). Concurrently, the free Gβ and Gγ subunits directly stimulate phosphatidylinositol 3-kinase (PI3K) and the kinase AKT, leading to phosphorylation and inactivation of GSK3β. Dissociated from its axin complex and inactivated, GSK3β can no longer phosphorylate and inactivate the transcription factor β-catenin.

Stabilized β-catenin can therefore translocate to the nucleus, where it interacts with the transcription factors TCF and LEF to activate genes that promote colon cancer cell proliferation. Identification of this novel signalling pathway provides alternative therapeutic strategies for colon cancer chemoprevention.