[Role of Prostaglandin Synthases in Carcinogenesis].

Prostaglandins (PGs) are oxygenated derivatives of arachidonic acid, synthesized through sequential catalysis involving cyclooxygenase (COX) and PG terminal synthases. Of the two COX enzymes, COX-2 is induced by inflammatory and pro-carcinogenic stimuli and it not only promotes inflammatory reactions but it also plays a role in the development of various tumors. Nonsteroidal anti-inflammatory drugs (NSAIDs), which suppress inflammatory responses by inhibiting COX, have also been reported to suppress carcinogenesis in the colon. However, long-term use of NSAIDs for the prevention of cancer causes several side-effects; therefore, an alternative COX target is required. In this review, the role of PG synthases that are produced downstream of COX in carcinogenesis will be explained and novel drug targets to inhibit carcinogenesis will be discussed. Microsomal PGE synthase (mPGES)-1 and prostacyclin synthase (PGIS), which are coupled with COX-2 to generate PGE2 and PGI2, respectively, promote inflammation. In mPGES-1 knock-out mice, carcinogenesis in the colon, skin, and bladder were suppressed. As mPGES-1 deficiency does not result in abnormalities, mPGES-1 inhibitors are expected to be promising alternatives to NSAIDs for the suppression of cancer. On the other hand, it has been reported that PGIS suppresses colon cancer, suggesting that it has an opposite role to mPGES-1 in carcinogenesis in the colon. However, PGIS not affect carcinogenesis in the skin. These results suggest that PGIS has differential effects on carcinogenesis in different tissues.