11β-hydroxysteroid dehydrogenase type II: a Potential target for prevention of colonic tumorigenesis

Abstract

Cancer is the second most common cause of death in the world, and primary prevention remains the best approach to reducing overall morbidity and mortality. There is a molecular link between cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) production and colonic tumorigenesis. Selective COX-2 inhibitors as well as non-steroidal anti-inflammatory drugs (NSAIDs) reduce the number and sizes of colonic adenomas; however, increased cardiovascular risks of selective COX-2 inhibitors and increased gastrointestinal side-effects of NSAIDs limit their use. Glucocorticoids induce cancer cell apoptosis and are endogenous, potent COX-2 inhibitors. In tissues, glucocorticoid actions are down-regulated by type 2 11ß-hydroxysteroid dehydrogenase (11ßHSD2), and inhibition of 11ßHSD2 activity will elevate intracellular active glucocorticoids to levels that effectively suppress COX-2 expression. Both COX-2 and 11ßHSD2 increase in Apc+/min mouse intestinal adenomas and human colonic adenomas, and either pharmacologic or genetic 11βHSD2 inhibition leads to decreases in COX-2-mediated PGE2 production in tumors and prevents adenoma formation, tumor growth, and metastasis. 11ßHSD2 inhibition may represent a novel approach for CRC chemoprevention by increasing tumor cell intracellular glucocorticoid activity, which in turn inhibits tumor growth by suppressing the COX-2-derived PGE2 pathway, as well as other pathways, without potential side-effects relating to chronic application of COX-2 inhibitors, NSAIDs and glucocorticoids.