Publication

Inhibition of 11beta-hydroxysteroid dehydrogenase type II selectively blocks the tumor COX-2 pathway and suppresses colon carcinogenesis in mice and humans.

Zhang MZ, Xu J, Yao B, Yin H, Cai Q, Shrubsole MJ, Chen X, Kon V, Zheng W, Pozzi A, Harris RC
J Clin Invest. 2009 119 (4): 876-85

PMID: 19307727 · PMCID: PMC2662561 · DOI:10.1172/JCI37398

Colorectal cancer (CRC) is a leading cause of cancer death, yet primary prevention remains the best approach to reducing overall morbidity and mortality. Studies have shown that COX-2-derived PGE2 promotes CRC progression, and both nonselective COX inhibitors (NSAIDs) and selective COX-2 inhibitors (such as glucocorticoids) reduce the number and size of colonic adenomas. However, increased gastrointestinal side effects of NSAIDs and increased cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention of CRC. We found that expression of 11beta-hydroxysteroid dehydrogenase type II (11betaHSD2), which converts active glucocorticoids to inactive keto-forms, increased in human colonic and Apc+/min mouse intestinal adenomas and correlated with increased COX-2 expression and activity. Furthermore, pharmacologic inhibition or gene silencing of 11betaHSD2 inhibited COX-2-mediated PGE2 production in tumors and prevented adenoma formation, tumor growth, and metastasis in mice. Inhibition of 11betaHSD2 did not reduce systemic prostacyclin production or accelerate atherosclerosis in mice, thereby avoiding the major cardiovascular side effects seen with systemic COX-2 inhibitors. Therefore, 11betaHSD2 inhibition represents what we believe to be a novel approach for CRC chemoprevention and therapy by increasing tumor glucocorticoid activity, which in turn selectively blocks local COX-2 activity.

MeSH Terms (22)

11-beta-Hydroxysteroid Dehydrogenase Type 2 Adenocarcinoma Adenoma Animals Base Sequence Cell Line, Tumor Colonic Neoplasms Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Enzyme Inhibitors Genes, APC Gene Silencing Glycyrrhizic Acid Humans Male Mice Mice, Inbred BALB C Mice, Mutant Strains Models, Biological Neovascularization, Pathologic Receptors, Glucocorticoid RNA, Small Interfering

Connections (7)

This publication is referenced by other Labnodes entities:

Links