Roles of Prostanoids in Colon Carcinogenesis and their Potential Targeting for Cancer Chemoprevention

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.