A previously unrecognized connection between two well-known signaling pathways appears to provide a crucial mechanism for control of proliferation of colon cancer cells. Castellone et al. show that the EP2 subtype of prostaglandin E2 receptor mounts a two-pronged attack that activates a transcriptional program that favors cell proliferation. When PGE2 binds to EP2, the associated heterotrimeric guanine nucleotide-binding protein (G protein) is activated. The G protein βγ and α subunits act through distinct pathways that converge to promote stabilization and nuclear translocation of β-catenin, a protein that promotes transcription of specific genes that increase proliferation of cancer cells. This signaling system may explain why nonsteroidal anti-inflammatory drugs, which inhibit signaling through PGE2, can at times inhibit development of colon cancer in mice and human patients.
M. D. Castellone, H. Teramoto, B. O. Williams, K. M. Druey, J. S. Gutkind, Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-β-catenin signaling axis. Science 310, 1504-1510 (2005). [Abstract] [Full Text]