Prostanoids are produced in response to numerous
growth factors and environmental stimuli. Their synthesis is dependent on two
cyclooxygenase (COX)
enzymes, COX-1 and COX-2, which are rate-limiting for the production of
prostaglandins (PGs) and
thromboxanes from free
arachidonic acid. Selective inhibitors of both COX forms have the potential to inhibit colon
tumorigenesis, and there is abundant documented evidence of elevated expression of COX-2 in colon
tumors and a variety of other
malignancies. The resultant high level
PGE2 production may play an important role in cell proliferation, modulation of apoptosis, angiogenesis,
inflammation and immune surveillance.
Prostanoids exert their biological actions through binding to eight specific membrane receptors; the four subtypes EP1 to EP4 for
PGE2; DP for
PGD2; FP for
PGF2; IP for PGI2; and TP for
thromboxane A2. Recently, genetic and pharmacologic experiments have suggested that all
PGE2 receptors can contribute to colon
tumorigenesis. Moreover, it is suggested that EP1 and EP4 play roles in
polyp formation independently. It is important to determine details of the down-stream signaling pathways of
prostanoid receptors for further understanding of the mechanisms of
cancer development. Furthermore, it is anticipated that development of specific receptor antagonists will provide new advantageous tools for
chemoprevention.